Analyte sensor

ABSTRACT

Systems and methods of use for continuous analyte measurement of a host&#39;s vascular system are provided. In some embodiments, a continuous glucose measurement system includes a vascular access device, a sensor and sensor electronics, the system being configured for insertion into a host&#39;s peripheral vein or artery.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 11/543,490, filed on Oct. 4, 2006. The aforementioned application isincorporated by reference herein in its entirety, and is herebyexpressly made a part of this specification.

FIELD OF THE INVENTION

The preferred embodiments relate generally to systems and methods formeasuring an analyte in a host.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which can cause anarray of physiological derangements associated with the deterioration ofsmall blood vessels, for example, kidney failure, skin ulcers, orbleeding into the vitreous of the eye. A hypoglycemic reaction (lowblood sugar) can be induced by an inadvertent overdose of insulin, orafter a normal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a person with diabetes carries a self-monitoring bloodglucose (SMBG) monitor, which typically requires uncomfortable fingerpricking methods. Due to the lack of comfort and convenience, a personwith diabetes normally only measures his or her glucose levels two tofour times per day. Unfortunately, such time intervals are so far spreadapart that the person with diabetes likely finds out too late of ahyperglycemic or hypoglycemic condition, sometimes incurring dangerousside effects. It is not only unlikely that a person with diabetes willtake a timely SMBG value, it is also likely that he or she will not knowif his or her blood glucose value is going up (higher) or down (lower)based on conventional methods. This inhibits the ability to makeeducated insulin therapy decisions.

A variety of sensors are known that use an electrochemical cell toprovide output signals by which the presence or absence of an analyte,such as glucose, in a sample can be determined. For example, in anelectrochemical cell, an analyte (or a species derived from it) that iselectro-active generates a detectable signal at an electrode, and thissignal can be used to detect or measure the presence and/or amountwithin a biological sample. In some conventional sensors, an enzyme isprovided that reacts with the analyte to be measured, and the byproductof the reaction is qualified or quantified at the electrode. An enzymehas the advantage that it can be very specific to an analyte and also,when the analyte itself is not sufficiently electro-active, can be usedto interact with the analyte to generate another species which iselectro-active and to which the sensor can produce a desired output. Inone conventional amperometric glucose oxidase-based glucose sensor,immobilized glucose oxidase catalyses the oxidation of glucose to formhydrogen peroxide, which is then quantified by amperometric measurement(for example, change in electrical current) through a polarizedelectrode.

SUMMARY OF THE INVENTION

In a first aspect, a system for measuring an analyte is provided, thesystem comprising a vascular access device in communication with avascular system of a host; and an analyte sensor configured to extendwithin the vascular access device, wherein the analyte sensor isconfigured to measure a concentration of an analyte within the vascularsystem.

In an embodiment of the first aspect, the analyte sensor is configuredto extend through the vascular access device and into a blood stream ofthe host.

In an embodiment of the first aspect, the vascular access device is acatheter.

In an embodiment of the first aspect, the vascular access device isconfigured for insertion into a vein of the host.

In an embodiment of the first aspect, the vascular access device isconfigured for insertion into an artery of the host.

In an embodiment of the first aspect, the vascular access device isconfigured to operatively couple to a pressure transducer formeasurement of a blood pressure of the host.

In an embodiment of the first aspect, the vascular access device isconfigured to operatively couple to a blood chemistry analysis devicefor measuring a blood chemistry of the host.

In an embodiment of the first aspect, the analyte sensor is a glucosesensor.

In an embodiment of the first aspect, the system further comprises asheath configured to protect the analyte sensor during insertion of theanalyte sensor into the catheter. The sheath can comprise a slotconfigured to allow the release of the analyte sensor therefrom.

In an embodiment of the first aspect, the system further comprises afluid coupler having first end and second end, wherein the fluid coupleris configured to mate with the vascular access device on the first end,and wherein at least a portion of the analyte sensor extends through thefluid coupler or is housed within the fluid coupler. The fluid couplercan comprise sensor electronics formed thereon. The sensor electronicscan a potentiostat. The fluid coupler can be configured to mate with amedical device on the second end. The medical device can comprise atleast one device selected from the group consisting of a blood pressuremonitor, a blood chemistry device, and a dialysis bypass machine.

In an embodiment of the first aspect, the analyte sensor is configuredto extend through the vascular access device and into a blood stream ofthe host by from about 0.010 inches to about 1 inch.

In an embodiment of the first aspect, the vascular access device and theanalyte sensor are configured to indwell within a blood stream of thehost in vivo.

In an embodiment of the first aspect, further comprising sensorelectronics operatively connected to the analyte sensor.

In an embodiment of the first aspect, the analyte sensor comprises atleast one working electrode configured to measure a first signal. Thefirst signal can be substantially analyte related.

In an embodiment of the first aspect, the analyte sensor furthercomprises a second working electrode configured to measure a secondsignal. The second signal can be substantially non-analyte related.

In an embodiment of the first aspect, the sensor electronics areconfigured to process the second signal and the first signal todetermine a concentration of an analyte.

In an embodiment of the first aspect, the sensor further comprises areference electrode.

In an embodiment of the first aspect, the reference electrode is locatedat a position remote from the working electrode.

In an embodiment of the first aspect, the sensor further comprises afluid coupler having first end and a second end, wherein the fluidcoupler is configured to mate with the catheter on the first end,wherein at least a portion of the analyte sensor extends through thefluid coupler or is housed within the fluid coupler, and wherein thereference electrode is located at a position proximal to the fluidcoupler or within the fluid coupler.

In an embodiment of the first aspect, an end of the analyte sensor thatextends into a blood stream of the host comprises an enlarged area.

In an embodiment of the first aspect, a substantial portion of theanalyte sensor has a diameter of less than about 0.008 inches.

In an embodiment of the first aspect, a substantial portion of theanalyte sensor has a diameter of less than about 0.004 inches.

In an embodiment of the first aspect, the analyte sensor furthercomprises a bioinert material or a bioactive agent incorporated thereinor thereon. The bioactive agent can comprise at least one agent selectedfrom the group consisting of vitamin K antagonists, heparin groupanticoagulants, platelet aggregation inhibitors, enzymes, directthrombin inhibitors, Dabigatran, Defibrotide, Dermatan sulfate,Fondaparinux, and Rivaroxaban.

In an embodiment of the first aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein at least one of theworking electrode and the reference electrode comprises a wire.

In an embodiment of the first aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thewires are coaxial.

In an embodiment of the first aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thewires are juxtapositioned.

In an embodiment of the first aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thereference electrode is helically wound around the working electrode.

In an embodiment of the first aspect, the analyte sensor comprises aworking electrode, and wherein the working electrode is flexible.

In an embodiment of the first aspect, the analyte sensor comprises aworking electrode, and wherein the working electrode has a variablestiffness.

In an embodiment of the first aspect, the analyte sensor comprises atleast one wire having a helical configuration, wherein a variablestiffness in the helical wire is provided by at least one of a variablepitch of the helical wire and a variable cross-section of the helicalwire.

In a second aspect, a method for measuring an analyte in a blood streamof a host is provided, the method comprising inserting a vascular accessdevice into communication with a blood stream of a host; and insertingan analyte sensor into the vascular access device, wherein the analytesensor measures a concentration of an analyte within the blood stream ofthe host.

In an embodiment of the second aspect, the analyte sensor extendsthrough the vascular access device and into the blood stream.

In an embodiment of the second aspect, the vascular access device is acatheter.

In an embodiment of the second aspect, the vascular access device isinserted into a vein of the host.

In an embodiment of the second aspect, the vascular access device isinserted into an artery of the host.

In an embodiment of the second aspect, the method further comprisescoupling a pressure transducer to the analyte sensor.

In an embodiment of the second aspect, the method further comprisescoupling a blood chemistry analysis device to the analyte sensor.

In an embodiment of the second aspect, the analyte sensor measuresglucose.

In an embodiment of the second aspect, the analyte sensor comprises afluid coupler for housing the analyte sensor or supporting the analytesensor, and wherein the method further comprises mating the fluidcoupler with the vascular access device on a first end of the fluidcoupler.

In an embodiment of the second aspect, the method further comprisesmating the fluid coupler with a medical device on a second end of thefluid coupler.

In an embodiment of the second aspect, the method further comprisesmeasuring at least one other parameter with the medical device, whereinthe parameter is selected from the group consisting of blood pressureand blood chemistry.

In an embodiment of the second aspect, the step of inserting the analytesensor comprises inserting the analyte sensor beyond an in vivo end ofthe vascular access device by from about 0.010 inches to about 1 inch.

In an embodiment of the second aspect, the vascular access device andthe analyte sensor are configured to indwell within a blood stream ofthe host in vivo.

In an embodiment of the second aspect, sensor electronics areoperatively connected to the analyte sensor, and wherein the methodfurther comprises utilizing sensor electronics to measure aconcentration of an analyte within the host.

In an embodiment of the second aspect, the analyte sensor comprises atleast one working electrode, and wherein the method further comprisesmeasuring a first signal at the working electrode, and wherein the firstsignal is substantially analyte-related.

In an embodiment of the second aspect, the analyte sensor furthercomprises a second working electrode, and wherein the method furthercomprises measuring a second signal at the second working electrode. Thesecond signal can be substantially non-analyte-related.

In an embodiment of the second aspect, the method further comprisesprocessing the second signal and the first signal to determine aconcentration of an analyte.

In an embodiment of the second aspect, the method further comprisesavoiding piercing of a blood vessel during sensor insertion into theblood vessel by providing an enlarged area at an insertion end of theanalyte sensor.

In an embodiment of the second aspect, the method further comprisessubstantially preventing clotting or thrombosis proximal to or on theanalyte sensor within the blood stream.

In a third aspect, a system for measuring an analyte is provided, thesystem comprising a vascular access device configured for insertioncommunication with a vascular system of a host, wherein the vascularaccess device comprises an analyte sensor at least partially integrallyincorporated therewith; and sensor electronics operatively connected tothe analyte sensor, wherein the sensor electronics are configured tomeasure a concentration of an analyte within the vascular system.

In an embodiment of the third aspect, the sensor electronics areconfigured to substantially continuously measure the analyteconcentration.

In an embodiment of the third aspect, the analyte is glucose.

In an embodiment of the third aspect, the vascular access device isconfigured to operatively couple to a blood chemistry analysis devicefor measuring a blood chemistry of the host.

In an embodiment of the third aspect, the analyte sensor comprises atleast one working electrode configured measure a first signal.

In an embodiment of the third aspect, the first signal is substantiallyanalyte related.

In an embodiment of the third aspect, the analyte sensor furthercomprises a second working electrode configured measure a second signal.

In an embodiment of the third aspect, the second signal is substantiallynon-analyte related.

In an embodiment of the third aspect, the sensor electronics areconfigured to process the second signal and the first signal todetermine a concentration of an analyte.

In an embodiment of the third aspect, the analyte sensor furthercomprises a reference electrode.

In an embodiment of the third aspect, the reference electrode is locatedat a position remote from the reference electrode.

In an embodiment of the third aspect, the reference electrode isconfigured to be located outside of a blood stream of the host.

In an embodiment of the third aspect, the analyte sensor furthercomprises a counter electrode.

In an embodiment of the third aspect, the analyte sensor is configuredto at least partially contact an in vivo blood stream of the host whenthe vascular access device is inserted therein.

In an embodiment of the third aspect, the analyte sensor is deposited onan exterior surface of the vascular access device.

In an embodiment of the third aspect, the analyte sensor iselectroplated onto the exterior surface of the vascular access device.

In an embodiment of the third aspect, the analyte sensor is wired to atleast a portion of the sensor electronics.

In an embodiment of the third aspect, the analyte sensor is wirelesslyconnected to at least a portion of the sensor electronics.

In an embodiment of the third aspect, the vascular access device is acatheter.

In an embodiment of the third aspect, the analyte sensor furthercomprises a bioinert material or a bioactive agent incorporatedtherewith. The bioactive agent can comprise at least one agent selectedfrom the group consisting of vitamin K antagonists, heparin groupanticoagulants, platelet aggregation inhibitors, enzymes, directthrombin inhibitors, Dabigatran, Defibrotide, Dermatan sulfate,Fondaparinux, and Rivaroxaban.

In an embodiment of the third aspect, the analyte sensor comprises aworking electrode and a reference electrode, and wherein at least one ofthe working electrode and the reference electrode comprises a wire.

In an embodiment of the third aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thewires are coaxial.

In an embodiment of the third aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thewires are juxtapositioned.

In an embodiment of the third aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thereference electrode is helically wound around the working electrode.

In an embodiment of the third aspect, the analyte sensor comprises aworking electrode, and wherein the working electrode is flexible.

In an embodiment of the third aspect, the analyte sensor comprises aworking electrode, and wherein the working electrode has a variablestiffness.

In an embodiment of the third aspect, the analyte sensor comprises atleast one wire having a helical configuration, and wherein a variablestiffness in the helical wire is provided by at least one of a variablepitch of the helical wire and a variable cross-section of the helicalwire.

In a fourth aspect, a method for measuring an analyte in a blood streamof a host is provided, the method comprising inserting a vascular accessdevice into communication with a blood stream of a host, wherein thevascular access device comprises an analyte sensor at least partiallyintegrally incorporated therewith; operatively connecting the analytesensor to sensor electronics; and measuring an analyte concentration inthe host.

In an embodiment of the fourth aspect, the method further comprisessubstantially continuously measuring an analyte concentration.

In an embodiment of the fourth aspect, the step of measuring an analyteconcentration comprises measuring a glucose concentration.

In an embodiment of the fourth aspect, the analyte sensor comprises atleast one working electrode, wherein the measuring step comprisesmeasuring a first signal at the working electrode, wherein the firstsignal is substantially analyte-related.

In an embodiment of the fourth aspect, the analyte sensor furthercomprises a second working electrode, and the measuring step furthercomprises measuring a second signal at the second working electrode,wherein the second signal is substantially non-analyte related.

In an embodiment of the fourth aspect, the method further comprisesprocessing the second signal and the first signal to determine aconcentration of an analyte.

In an embodiment of the fourth aspect, the measuring step comprisesmeasuring an analyte concentration in an in vivo blood stream of thehost.

In an embodiment of the fourth aspect, the operatively connecting stepcomprises connecting the analyte sensor to at least a portion of thesensor electronics via a wired connection.

In an embodiment of the fourth aspect, the operatively connecting stepcomprises connecting the analyte sensor to at least a portion of thesensor electronics via a wireless connection.

In a fifth aspect, a method for manufacturing an analyte sensorconfigured for measuring an analyte in a vascular system of a host isprovided, the method comprising providing a vascular access device; andat least partially integrally incorporating an analyte sensor in thevascular access device or on a surface of the vascular access device.

In an embodiment of the fifth aspect, the step of at least partiallyintegrally incorporating an analyte sensor comprises depositing at leastone working electrode on an interior surface of the vascular accessdevice or on an exterior surface of the vascular access device.

In an embodiment of the fifth aspect, the depositing step furthercomprises electroplating the working electrode onto the exterior surfaceof the vascular access device.

In an embodiment of the fifth aspect, the step of at least partiallyintegrally incorporating an analyte sensor further comprises depositinga second working electrode on an interior surface of the vascular accessdevice or on an exterior surface of the vascular access device.

In an embodiment of the fifth aspect, the step of at least partiallyintegrally incorporating an analyte sensor further comprises depositinga reference electrode on an interior surface of the vascular accessdevice or on an exterior surface of the vascular access device.

In an embodiment of the fifth aspect, the step of at least partiallyintegrally incorporating an analyte sensor further comprises depositinga counter electrode on an interior surface of the vascular access deviceor on an exterior surface of the vascular access device.

In an embodiment of the fifth aspect, the surface of the vascular accessdevice is selected from the group consisting of an exterior surface, aninterior surface, and a tip surface.

In an embodiment of the fifth aspect, the step of at least partiallyintegrally incorporating an analyte sensor further comprises forming areference electrode at a location remote from the working electrode.

In a sixth aspect, a method for calibrating a continuous analyte sensorin a host is provided, the method comprising inserting a continuousanalyte sensor into a host; contacting a calibration solution with atleast a portion of the continuous analyte sensor; and calibrating thecontinuous analyte sensor to provide calibrated analyte sensor datacomprising at least one calibrated sensor data point.

In an embodiment of the sixth aspect, the continuous analyte sensor isconfigured to indwell within a blood stream of a host.

In an embodiment of the sixth aspect, the continuous analyte sensor isconfigured to measure a glucose concentration in the host.

In an embodiment of the sixth aspect, the calibration solution comprisesa predetermined amount of glucose.

In an embodiment of the sixth aspect, the method further comprisesdisplaying the calibrated analyte sensor data.

In an embodiment of the sixth aspect, the method further comprisescontacting an additional calibration solution with at least a portion ofthe continuous analyte sensor.

In an embodiment of the sixth aspect, the method further comprisescalibrating or re-calibrating the continuous analyte sensor to providecalibrated analyte sensor data comprising at least one calibrated sensordata point.

In an embodiment of the sixth aspect, the step of contacting anadditional calibration solution is repeated.

In an embodiment of the sixth aspect, the step of contacting anadditional calibration solution is performed automatically.

In an embodiment of the sixth aspect, the step of contacting anadditional calibration solution is performed manually.

In an embodiment of the sixth aspect, the method further comprisescontacting a non-analyte solution with at least a portion of thecontinuous analyte sensor to flush the sensor.

In an embodiment of the sixth aspect, the step of contacting anon-analyte solution is performed prior to the step of contacting acalibration solution with at least a portion of the continuous analytesensor.

In a seventh aspect, a method for calibrating a continuous analytesensor in a host is provided, the method comprising inserting acontinuous analyte sensor system into a host; withdrawing at least oneblood sample from the host; measuring a reference analyte value from theblood sample; and calibrating the continuous analyte sensor to providecalibrated analyte sensor data comprising at least one calibrated sensordata point.

In an embodiment of the seventh aspect, the continuous analyte sensor isconfigured to indwell within a blood stream of the host.

In an embodiment of the seventh aspect, the continuous analyte sensor isconfigured to measure a glucose concentration of the host.

In an embodiment of the seventh aspect, the step of withdrawing at leastone blood sample from the host is performed automatically.

In an embodiment of the seventh aspect, the step of inserting acontinuous analyte sensor comprises inserting a vascular access deviceinto communication with a vascular system of the host, wherein thesensor is integrally incorporated with the vascular access device.

In an embodiment of the seventh aspect, the step of withdrawingcomprises withdrawing a blood sample through the vascular access device.

In an embodiment of the seventh aspect, the method further comprisesinserting a vascular access device into communication with a vascularsystem of the host, wherein the sensor is inserted through the vascularaccess device.

In an embodiment of the seventh aspect, the step of withdrawingcomprises withdrawing a blood sample through the vascular access device.

In an embodiment of the seventh aspect, the method further comprisesdisplaying the calibrated sensor data.

In an embodiment of the seventh aspect, the method further comprisescoupling a blood chemistry device to the continuous analyte sensorsystem.

In an embodiment of the seventh aspect, the blood chemistry deviceperforms the step of analyzing at least one blood sample from the host.

In an embodiment of the seventh aspect, the blood chemistry deviceperforms the step of measuring a reference analyte value from the bloodsample.

In an eighth aspect, a continuous analyte sensor system is provided, thesystem comprising a continuous analyte sensor configured for insertioninto a host; and a computer system operatively connected to thecontinuous analyte sensor, wherein the computer system is configured toreceive analyte sensor data from the continuous analyte sensor, theanalyte sensor data comprising at least one sensor data point andcalibration information, and wherein the computer system is configuredto calibrate the analyte sensor data from the calibration information.

In an embodiment of the eighth aspect, the analyte sensor is a glucosesensor.

In an embodiment of the eighth aspect, the continuous analyte sensorcomprises a vascular access device configured for communication with avascular system of the host, and wherein the continuous analyte sensoris configured to extend through the vascular access device, wherein theanalyte sensor is configured to measure a concentration of an analytewithin a vascular system of the host.

In an embodiment of the eighth aspect, the vascular access device isconfigured to operatively couple to a blood chemistry analysis devicefor measuring a blood chemistry of the host.

In an embodiment of the eighth aspect, the blood chemistry device isconfigured to withdraw a blood sample through the vascular accessdevice, and wherein the calibration information comprises the bloodsample or a measurement associated therewith.

In an embodiment of the eighth aspect, the blood chemistry device isconfigured to measure a reference analyte value from the host, andwherein the calibration information comprises the reference analytevalue.

In an embodiment of the eighth aspect, the system further comprises adevice configured to automatically obtain the calibration information,wherein the device is operatively coupled to the sensor system.

In an embodiment of the eighth aspect, the continuous analyte sensorcomprises a vascular access device configured for communication with avascular system of the host, wherein the vascular access devicecomprises an analyte sensor at least partially integrally incorporatedon an exterior surface the vascular access device and further comprisessensor electronics operatively connected to the analyte sensor, whereinthe sensor electronics are configured to measure a concentration of ananalyte within a blood stream of the host.

In an embodiment of the eighth aspect, the vascular access device isconfigured to operatively couple to a blood chemistry analysis devicefor measuring a blood chemistry of the host.

In an embodiment of the eighth aspect, the blood chemistry device isconfigured to withdraw a blood sample through the vascular accessdevice, and wherein the calibration information comprises the bloodsample or a measurement associated therewith.

In an embodiment of the eighth aspect, the blood chemistry device isconfigured to measure a reference analyte value from the host, andwherein the calibration information comprises the reference analytevalue.

In an embodiment of the eighth aspect, the system further comprises adevice configured to automatically obtain the calibration information,wherein the device is operatively coupled to the sensor system.

In an embodiment of the eighth aspect, the analyte sensor comprises aworking electrode and a reference electrode, and wherein at least one ofthe working electrode and the reference electrode comprises a wire.

In an embodiment of the eighth aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thewires are coaxial.

In an embodiment of the eighth aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thewires are juxtapositioned.

In an embodiment of the eighth aspect, the analyte sensor comprises aworking electrode and a reference electrode, wherein the workingelectrode and the reference electrode are both wires, and wherein thereference electrode is helically wound around the working electrode.

In an embodiment of the eighth aspect, the analyte sensor comprises aworking electrode, and wherein the working electrode is flexible.

In an embodiment of the eighth aspect, the analyte sensor comprises aworking electrode, and wherein the working electrode has a variablestiffness.

In an embodiment of the eighth aspect, the analyte sensor comprises atleast one wire having a helical configuration, and wherein a variablestiffness in the helical wire is provided by at least one of a variablepitch of the helical wire and a variable cross-section of the helicalwire.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of one embodiment of an analyte sensorsystem, including a vascular access device (e.g., a catheter), a sensor,a fluid connector, and a protective sheath.

FIG. 1B is a side view of the analyte sensor system of FIG. 1A, showingthe protective sheath removed.

FIG. 1C1 is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1C2 is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1D is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 1E is a close-up cut away view of a portion of the analyte sensorsystem of FIG. 1A.

FIG. 2A is a perspective view of another embodiment of the analytesensor system, including a catheter with a sensor integrally formedthereon.

FIG. 2B is a perspective view of the analyte sensor system of FIG. 2A.

FIG. 2C is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative configuration of an embodiment having threeelectrodes disposed on the catheter.

FIG. 2D is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative configuration of an embodiment having threeelectrodes disposed on the catheter.

FIG. 2E is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative embodiment having two electrodes disposed onthe catheter.

FIG. 2F is a close-up view of a portion of the analyte sensor system ofFIG. 2A in an alternative embodiment having one electrode disposed onthe catheter.

FIG. 3A is a perspective view of a first portion of one embodiment of ananalyte sensor.

FIG. 3B is a perspective view of a second portion of the analyte sensorof FIG. 3A.

FIG. 3C is a cross section of the analyte sensor of FIG. 3B, taken online C-C.

FIG. 4 is a graph illustrating in vivo function of an analyte sensorsystem of the embodiment shown in FIG. 1A.

FIG. 5 is a graph illustrating in vivo function of an analyte sensorsystem of the embodiment shown in FIG. 1A.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate some exemplaryembodiments of the disclosed invention in detail. Those of skill in theart will recognize that there are numerous variations and modificationsof this invention that are encompassed by its scope. Accordingly, thedescription of a certain exemplary embodiment should not be deemed tolimit the scope of the preferred embodiments.

DEFINITIONS

In order to facilitate an understanding of the preferred embodiments, anumber of terms are defined below.

The term “analyte” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological fluid (for example, blood, interstitial fluid, cerebralspinal fluid, lymph fluid or urine) that can be analyzed. Analytes caninclude naturally occurring substances, artificial substances,metabolites, and/or reaction products. In some embodiments, the analytefor measurement by the sensing regions, devices, and methods is glucose.However, other analytes are contemplated as well, including but notlimited to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acidprofiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine,phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine;arabinitol enantiomers; arginase; benzoylecgonine (cocaine);biotimidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4;ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol;cholinesterase; conjugated 1-β hydroxy-cholic acid; cortisol; creatinekinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylatorpolymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cysticfibrosis, Duchenne/Becker muscular dystrophy, glucose-6-phosphatedehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D,hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis Bvirus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD,RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol);desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanusantitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D;fatty acids/acylglycines; free β-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, β);lysozyme; mefloquine; netilmicin; phenobarbitone; phenyloin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), histamine, AdvancedGlycation End Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).

The term “host” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to animals or plants, for example humans.

The term “continuous (or continual) analyte sensing” as used herein is abroad term, and is to be given its ordinary and customary meaning to aperson of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to theperiod in which monitoring of analyte concentration is continuously,continually, and or intermittently (regularly or irregularly) performed,for example, about every 5 to 10 minutes.

The term “electrochemically reactive surface” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a surface where anelectrochemical reaction takes place. For example, a working electrodemeasures hydrogen peroxide produced by the enzyme-catalyzed reaction ofthe analyte detected, which reacts to create an electric current.Glucose analyte can be detected utilizing glucose oxidase, whichproduces H₂O₂ as a byproduct. H₂O₂ reacts with the surface of theworking electrode, producing two protons (2H⁺), two electrons (2e⁻) andone molecule of oxygen (O₂), which produces the electronic current beingdetected.

The terms “electronic connection,” “electrical connection,” “electricalcontact” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), and referwithout limitation to any connection between two electrical conductorsknown to those in the art. In one embodiment, electrodes are inelectrical connection with the electronic circuitry of a device.

The term “sensing region” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region of a monitoringdevice responsible for the detection of a particular analyte. Thesensing region generally comprises a non-conductive body, a workingelectrode (anode), and can include a reference electrode (optional),and/or a counter electrode (cathode) forming electrochemically reactivesurfaces on the body.

The term “domain” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a region of the membrane system that can bea layer, a uniform or non-uniform gradient (for example, an anisotropicregion of a membrane), or a portion of a membrane.

The term “distal to” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the spatial relationship between variouselements in comparison to a particular point of reference. In general,the term indicates an element is located relatively far from thereference point than another element.

The term “proximal to” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. In general, the term indicates an element is locatedrelatively near to the reference point than another element.

The term “in vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device (forexample, a sensor) adapted for insertion into and/or existence within aliving body of a host.

The term “ex vivo portion” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a portion of a device (forexample, a sensor) adapted to remain and/or exist outside of a livingbody of a host.

The terms “raw data,” “raw data stream”, “raw data signal”, and “datastream” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefer without limitation to an analog or digital signal from the analytesensor directly related to the measured analyte. For example, the rawdata stream is digital data in “counts” converted by an A/D converterfrom an analog signal (for example, voltage or amps) representative ofan analyte concentration. The terms can include a plurality of timespaced data points from a substantially continuous analyte sensor, eachof which comprises individual measurements taken at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes or longer. In some embodiments, the terms can refer to data thathas been integrated or averaged over a time period (e.g., 5 minutes).

The term “count” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.For example, a raw data stream or raw data signal measured in counts isdirectly related to a voltage (for example, converted by an A/Dconverter), which is directly related to current from the workingelectrode. In some embodiments, the terms can refer to data that hasbeen integrated or averaged over a time period (e.g., 5 minutes).

The terms “sensor” and “sensor system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a device,component, or region of a device by which an analyte can be quantified.

The term “needle” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to a slender hollow instrument for introducingmaterial into or removing material from the body.

The terms “operatively connected,” “operatively linked,” “operablyconnected,” and “operably linked” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to one or morecomponents linked to one or more other components. The terms can referto a mechanical connection, an electrical connection, or any connectionthat allows transmission of signals between the components. For example,one or more electrodes can be used to detect the amount of analyte in asample and to convert that information into a signal; the signal canthen be transmitted to a circuit. In such an example, the electrode is“operably linked” to the electronic circuitry. The terms include wiredand wireless connections.

The terms “membrane” and “membrane system” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to apermeable or semi-permeable membrane that can be comprised of one ormore domains and is typically constructed of materials of one or moremicrons in thickness, which is permeable to oxygen and to an analyte,e.g., glucose or another analyte. In one example, the membrane systemcomprises an immobilized glucose oxidase enzyme, which enables areaction to occur between glucose and oxygen whereby a concentration ofglucose can be measured.

The terms “processor module” and “microprocessor” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to acomputer system, state machine, processor, and the like designed toperform arithmetic or logic operations using logic circuitry thatresponds to and processes the basic instructions that drive a computer.

The term “calibration” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the relationship and/orprocess of determining the relationship between the sensor data and thecorresponding reference data, which can be used to convert sensor datainto values substantially equivalent to the reference data. In someembodiments, namely, in continuous analyte sensors, calibration can beupdated or recalibrated over time if changes in the relationship betweenthe sensor data and reference data occur, for example, due to changes insensitivity, baseline, transport, metabolism, and the like.

The terms “interferents” and “interfering species” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to effectsand/or species that interfere with the measurement of an analyte ofinterest in a sensor to produce a signal that does not accuratelyrepresent the analyte concentration. In one example of anelectrochemical sensor, interfering species are compounds with anoxidation potential that substantially overlaps that of the analyte tobe measured, thereby producing a false positive signal.

The term “single point glucose monitor” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a device that canbe used to measure a glucose concentration within a host at a singlepoint in time, for example, some embodiments utilize a small volume invitro glucose monitor that includes an enzyme membrane such as describedwith reference to U.S. Pat. No. 4,994,167 and U.S. Pat. No. 4,757,022.It should be understood that single point glucose monitors can measuremultiple samples (for example, blood, or interstitial fluid); howeveronly one sample is measured at a time and typically requires some userinitiation and/or interaction.

The term “biological sample” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to sample of a host body, forexample blood, interstitial fluid, spinal fluid, saliva, urine, tears,sweat, tissue, fat, and the like.

The terms “substantial” and “substantially” as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount that provides a desired function. For example, anamount greater than 50 percent, an amount greater than 60 percent, anamount greater than 70 percent, an amount greater than 80 percent, or anamount greater than 90 percent.

The term “casting” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a process where a fluid material is appliedto a surface or surfaces and allowed to cure or dry. The term is broadenough to encompass a variety of coating techniques, for example, usinga draw-down machine (i.e., drawing-down), dip coating, spray coating,spin coating, and the like.

The term “dip coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating, which involvesdipping an object or material into a liquid coating substance.

The term “spray coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to coating, which involvesspraying a liquid coating substance onto an object or material.

The term “spin coating” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to a coating process in which athin film is created by dropping a raw material solution onto asubstrate while it is rotating.

The terms “solvent” and “solvent system” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to substances (e.g.,liquids) capable of dissolving or dispersing one or more othersubstances. Solvents and solvent systems can include compounds and/orsolutions that include components in addition to the solvent itself.

The term “baseline,” “noise” and “background signal” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and is not to be limited to aspecial or customized meaning), and refers without limitation to acomponent of an analyte sensor signal that is not related to the analyteconcentration. In one example of a glucose sensor, the baseline iscomposed substantially of signal contribution due to factors other thanglucose (for example, interfering species, non-reaction-related hydrogenperoxide, or other electroactive species with an oxidation potentialthat overlaps with hydrogen peroxide). In some embodiments wherein acalibration is defined by solving for the equation y=m×+b, the value ofb represents the baseline, or background, of the signal.

The terms “sensitivity” and “slope” as used herein are broad terms, andare to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to an amount ofelectrical current produced by a predetermined amount (unit) of themeasured analyte. For example, in one preferred embodiment, a glucosesensor has a sensitivity (or slope) of about 3.5 to about 7.5 picoAmpsof current for every 1 mg/dL of glucose.

The terms “baseline and/or sensitivity shift,” “baseline and/orsensitivity drift,” “shift,” and “drift” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to a change in thebaseline and/or sensitivity of the sensor signal over time. While theterm “shift” generally refers to a substantially distinct change over arelatively short time period, and the term “drift” generally refers to asubstantially gradual change over a relatively longer time period, theterms can be used interchangeably and can also be generally referred toas “change” in baseline and/or sensitivity.

The term “hypoglycemia” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a condition in which alimited or low amount of glucose exists in a host. Hypoglycemia canproduce a variety of symptoms and effects but the principal problemsarise from an inadequate supply of glucose as fuel to the brain,resulting in impairment of function (neuroglycopenia). Derangements offunction can range from vaguely “feeling bad” to coma, and (rarely)permanent brain damage or death.

The term “hyperglycemia” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a condition in which anexcessive or high amount of glucose exists in a host. Hyperglycemia isone of the classic symptoms of diabetes mellitus. Non-diabetichyperglycemia is associated with obesity and certain eating disorders,such as bulimia nervosa. Hyperglycemia is also associated with otherdiseases (or medications) affecting pancreatic function, such aspancreatic cancer. Hyperglycemia is also associated with poor medicaloutcomes in a variety of clinical settings, such as intensive orcritical care settings.

The term “potentiostat” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an electronic instrument thatcontrols the electrical potential between the working and referenceelectrodes at one or more preset values. Typically, a potentiostat worksto keep the potential constant by noticing changes in the resistance ofthe system and compensating inversely with a change in the current. As aresult, a change to a higher resistance would cause the current todecrease to keep the voltage constant in the system. In someembodiments, a potentiostat forces whatever current is necessary to flowbetween the working and counter electrodes to keep the desiredpotential, as long as the needed cell voltage and current do not exceedthe compliance limits of the potentiostat.

The terms “electronics” and “sensor electronics” as used herein arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toelectronics operatively coupled to the sensor and configured to measure,process, receive, and/or transmit data associated with a sensor. In someembodiments, the electronics include at least a potentiostat thatprovides a bias to the electrodes and measures a current to provide theraw data signal. The electronics are configured to calculate at leastone analyte sensor data point. For example, the electronics can includea potentiostat, A/D converter, RAM, ROM, and/or transmitter. In someembodiments, the potentiostat converts the raw data (e.g., raw counts)collected from the sensor and converts it to a value familiar to thehost and/or medical personnel. For example, the raw counts from aglucose sensor can be converted to milligrams of glucose per deciliterof blood (e.g., mg/dl). In some embodiments, the sensor electronicsinclude a transmitter that transmits the signals from the potentiostatto a receiver, where additional data analysis and glucose concentrationdetermination can occur.

The terms “coupling” and “operatively coupling” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to ajoining or linking together of two or more things, such as two parts ofa device or two devices, such that the things can function together. Inone example, two containers can be operatively coupled by tubing, suchthat fluid can flow from one container to another. Coupling does notimply a physical connection. For example, a transmitter and a receivercan be operatively coupled by radio frequency (RF)transmission/communication.

The term “fluid communication” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to two or more components (e.g.,things such as parts of a body or parts of a device) functionally linkedsuch that fluid can move from one component to another. These terms donot imply directionality.

The terms “continuous” and “continuously” as used herein are broadterms, and are to be given their ordinary and customary meanings to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to thecondition of being marked by substantially uninterrupted extension inspace, time or sequence. In one embodiment, an analyte concentration ismeasured continuously or continually, for example at time intervalsranging from fractions of a second up to, for example, 1, 2, or 5minutes, or longer. It should be understood that continuous glucosesensors generally continually measure glucose concentration withoutrequired user initiation and/or interaction for each measurement, suchas described with reference to U.S. Pat. No. 6,001,067, for example.These terms include situations wherein data gaps can exist (e.g., when acontinuous glucose sensor is temporarily not providing data).

The term “medical device” as used herein is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to an instrument, apparatus,implement, machine, contrivance, implant, in vitro reagent, or othersimilar or related article, including a component part, or accessorywhich is intended for use in the diagnosis of disease or otherconditions, or in the cure, mitigation, treatment, or prevention ofdisease, in man or other animals, or intended to affect the structure orany function of the body of man or other animals. Medical devices thatcan be used in conjunction with various embodiments of the analytesensor system include any monitoring device requiring placement in ahuman vessel, duct or body cavity, a dialysis machine, a heart-lungbypass machine, blood collection equipment, a blood pressure monitor, anautomated blood chemistry analysis device and the like.

The term “blood pressure monitor” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to an instrument for monitoringthe blood pressure of a human or other animal. For example, a bloodpressure monitor can be an invasive blood pressure monitor, whichperiodically monitors the host's blood pressure via a peripheral artery,using a blood pressure transducer, such as but not limited to adisposable blood pressure transducer. Utah Medical Products Inc.(Midvale, Utah, USA) produces a variety of Deltran® Brand disposableblood pressure transducers that are suitable for use with variousembodiments disclosed herein.

The term “pressure transducer” as used herein is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to a component of anintra-arterial blood pressure monitor that measures the host's bloodpressure.

The term “blood chemistry analysis device” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refers without limitation to a device thatmeasures a variety of blood components, characteristics or analytestherein. In one embodiment, a blood chemistry analysis deviceperiodically withdraws an aliquot of blood from the host, measuresglucose, O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH, lactate, urea,bilirubin, creatinine, hematocrit, various minerals, and/or variousmetabolites, and the like, and returns the blood to the host'scirculatory system. A variety of devices exist for testing various bloodproperties/analytes at the bedside, such as but not limited to the bloodgas and chemistry devices manufactured by Via Medical (Austin, Tex.,USA).

The term “vascular access device” as used herein is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and are not to be limited to a special or customizedmeaning), and refers without limitation to any device that is incommunication with the vascular system of a host. Vascular accessdevices include but are not limited to catheters, shunts, bloodwithdrawal devices and the like.

The term “catheter” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to a tube that can be inserted into a host'sbody (e.g., cavity, duct or vessel). In some circumstances, cathetersallow drainage or injection of fluids or access by medical instrumentsor devices. In some embodiments, a catheter is a thin, flexible tube(e.g., a “soft” catheter). In alternative embodiments, the catheter canbe a larger, solid tube (e.g., a “hard” catheter). The term “cannula” isinterchangeable with the term “catheter” herein.

The term “indwell” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and are not to be limited to a special or customized meaning), andrefers without limitation to reside within a host's body. Some medicaldevices can indwell within a host's body for various lengths of time,depending upon the purpose of the medical device, such as but notlimited to a few hours, days, weeks, to months, years, or even thehost's entire lifetime. In one exemplary embodiment, an arterialcatheter may indwell within the host's artery for a few hours, days, aweek, or longer, such as but not limited to the host's perioperativeperiod (e.g., from the time the host is admitted to the hospital to thetime he is discharged).

The term “sheath” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a covering or supporting structure thatfits closely around something, for example, in the way that a sheathcovers a blade. In one exemplary embodiment, a sheath is a slender,flexible, polymer tube that covers and supports a wire-type sensor priorto and during insertion of the sensor into a catheter.

The term “slot” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefers without limitation to a relatively narrow opening.

Overview

Intensive care medicine or critical care medicine is concerned withproviding greater than ordinary medical care and/or observation topeople in a critical or unstable condition. In recent years, anincreasingly urgent need has arisen, for more intensive care medicine.People requiring intensive care include those recovering after majorsurgery, with severe head trauma, life-threatening acute illness,respiratory insufficiency, coma, haemodynamic insufficiency, severefluid imbalance or with the failure of one or more of the major organsystems (life-critical systems or others). More than 5 million peopleare admitted annually to intensive care units (ICUs) and critical careunits (CCUs) in the United States.

Intensive care is generally the most expensive, high technology andresource intensive area of medical care. In the United States estimatesof the year 2000 expenditure for critical care medicine ranged from$15-55 billion accounting for about 0.5% of GDP and about 13% ofnational health care expenditure. As the U.S. population ages, thesecosts will increase substantially. Accordingly, there is an urgent needto reducing costs while at the same time reducing ICU/CCU mortalityrates by improving care. Some embodiments disclosed herein are suitablefor use in an intensive care or critical care unit of a medical carefacility for substantially continuously measuring a host's analyteconcentration.

Hyperglycemia is a medical condition in which an excessive amount ofglucose circulates in a host. Medical studies suggest a relationshipbetween hyperglycemia and host outcome in intensive/critical caresettings. For example, perioperative hyperglycemia is associated withincreased rates and severity of myocardial infarction (MI) and stroke,while tight glucose control with intravenous (IV) insulin therapy islinked to a 30% reduction in mortality one year after admission foracute MI. Furthermore, strict in-hospital glucose control is associatedwith 40% reductions of morbidity, mortality, sepsis, dialysis, bloodtransfusions, as well as reduced length of stay, reduced costs and thelike.

Hyperglycemia can also be an issue in non-critical care settings, suchas in the general hospital population, such as for diabetes hostsadmitted for non-glucose-related medical conditions, or in clinicalsettings, such as the doctor's office, such as during glucose challengetests, or treatment of the elderly or the very young, or others who mayhave difficulty with glucose control.

Unfortunately, using generally available technology, tight glucosecontrol requires frequent monitoring of the host by the clinical staff,IV insulin or injections, and on-time feeding. Frequent monitoringtypically requires a nurse or other staff member to measure the host'sglucose concentration using a lancet (to obtain a blood sample) and ahand held glucose monitor. The nurse can perform this task many times aday (e.g., every hour or more frequently). This task becomes an undueburden that takes the nurse away from his/her other duties, or requiresextra staff. The preferred embodiments disclose systems and methods toreduce and/or minimize the interaction required to regularly (e.g.,continuously) measure the host's glucose concentration.

Unfortunately it has been shown that an effort to maintain tight controlof glucose levels (e.g., about 80-129 mg/dl) can increase the risk ofhypoglycemia using conventional systems and methods. For example,administration of insulin, quality, and timing of meal ingestion, andthe like can lead to hypoglycemia. Because hypoglycemia can cause shockand death (immediate problems), the clinical staff rigorously avoids it,often by maintaining the host at elevated blood glucose concentrations(which can degrade the clinical outcome in the long run) and causes theproblems of hyperglycemia discussed above.

Accordingly, in spite of clinically demonstrated improvements associatedwith tight glucose control, institutions are slow to adopt the therapydue to the increased workload on the staff as well as a pervasive fearof hypoglycemia, which is potentially life ending. Therefore, there isan urgent need for devices and methods that offer continuous, robustglucose monitoring, to improve patient care and lower medical costs. Thepreferred embodiments describe systems and methods for providingcontinuous glucose monitoring while providing alarms or alerts that aidin avoiding hypoglycemic events.

Hyperglycemia can be managed in a variety of ways. Currently, for hostsin an intensive care setting, such as and ICU, CCU or emergency room(ER), hyperglycemia is managed with sliding-scale IV insulin, that stopsinsulin delivery at about 150 to 200 mg/dl. This generally requiresmonitoring by a nurse (using a hand-held clinical glucose meter) andinsulin administration at least every six hours. Maintaining tightglucose control within the normal range (e.g., 80-110 mg/dl) currentlyrequires hourly or even more frequent monitoring and insulinadministration. This places an undue burden on the nursing staff. Thepreferred embodiments provide devices and methods for automated,continuous glucose monitoring (e.g., indwelling in the circulatorysystem), to enable tight glucose control.

The in vivo continuous analyte monitoring system of the preferredembodiments can be used in clinical settings, such as in the hospital,the doctor's office, long-term nursing facilities, or even in the home.The present device can be used in any setting in which frequent orcontinuous analyte monitoring is desirable. For example, in the ICU,hosts are often recovering from serious illness, disease, or surgery,and control of host glucose levels is important for host recovery. Useof an in-dwelling continuous glucose monitor allows tight control ofhost glucose concentration and improved host care, while reducinghypoglycemic episodes and reducing the ICU staff work load. For example,the system can be used for the entire hospital stay or for only a partof the hospital stay.

In another example, the in-dwelling continuous glucose monitor can beused in an ER setting. In the ER, a host may be unable to communicatewith the staff. Routine use of a continuous analyte monitor (e.g.,glucose, creatinine, phosphate, electrolytes, or drugs) can enable theER staff to monitor and respond to analyte concentration changesindicative of the host's condition (e.g., the host's glucoseconcentration) without host input.

In yet another example, a continuous analyte monitor can be used in thegeneral hospital population to monitor host analyte concentrations, forvarious lengths of time, such as during the entire hospital stay or fora portion of the hospital stay (e.g., only during surgery). For example,a diabetic host's glucose concentration can be monitored during hisentire stay. In another example, a cardiac host's glucose can bemonitored during surgery and while in the ICU, but not after being movedto the general host population. In another example, a jaundiced newborninfant can have his bilirubin concentration continuously monitored by anin-dwelling continuous analyte monitor until the condition has receded.

In addition to use in the circulatory system, the analyte sensor of thepreferred embodiments can be used in other body locations. In someembodiments, the sensor is used subcutaneously. In another embodiment,the sensor can be used intracranially. In another embodiment, the sensorcan be used within the spinal compartment, such as but not limited tothe epidural space. In some embodiments, the sensor of the preferredembodiments can be used with or without a catheter.

Applications/Uses

One aspect of the preferred embodiments provides a system for in vivocontinuous analyte monitoring (e.g., glucose, O₂, CO₂, PCO₂, PO₂,potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit,various minerals, various metabolites, and the like) that can beoperatively coupled to a catheter to measure analyte concentrationwithin the host's blood stream. In some embodiments, the system includesan analyte sensor that extends a short distance into the blood stream(e.g., out of the catheter) without substantially occluding the catheteror the host's blood stream. The catheter can be fluidly coupled toadditional IV and diagnostic devices, such as a saline bag, an automatedblood pressure monitor, or a blood chemistry monitor device. In someembodiments, blood samples can be removed from the host via the sensorsystem, as described elsewhere herein. In one embodiment, the sensor isa glucose sensor, and the medical staff monitors the host's glucoselevel.

FIGS. 1A to 1E illustrate one embodiment of an exemplary analyte sensorsystem 10 for measuring an analyte (e.g., glucose, urea, potassium, pH,proteins, etc.) that includes a catheter 12 configured to be inserted orpre-inserted into a host's blood stream. In clinical settings, cathetersare often inserted into hosts to allow direct access to the circulatorysystem without frequent needle insertion (e.g., venipuncture). Suitablecatheters can be sized as is known and appreciated by one skilled in theart, such as but not limited to from about 1 French (0.33 mm) or less toabout 30 French (10 mm) or more; and can be, for example, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 French (3 Frenchis equivalent to about 1 mm). The catheter can be manufactured of anymedical grade material known in the art, such as but not limited topolymers and glass as described herein. A catheter can include a singlelumen or multiple lumens. A catheter can include one or moreperforations, to allow the passage of host fluid through the lumen ofthe catheter.

The terms “inserted” or “pre-inserted” as used herein are broad terms,and are to be given their ordinary and customary meaning to a person ofordinary skill in the art (and are not to be limited to a special orcustomized meaning), and refer without limitation to insertion of onething into another thing. For example, a catheter can be inserted into ahost's blood stream. In some embodiments, a catheter is “pre-inserted,”meaning inserted before another action is taken (e.g., insertion of acatheter into a host's blood stream prior to insertion of a sensor intothe catheter). In some exemplary embodiments, a sensor is coupled to apre-inserted catheter, namely, one that has been previously inserted (orpre-inserted) into the host's circulatory system.

Referring now to FIGS. 1A to 1E, in some embodiments, the catheter 12 isa thin, flexible tube having a lumen 12 a, such as is known in the art.In some embodiments, the catheter can be rigid; in other embodiments,the catheter can be custom manufactured to desired specifications (e.g.,rigidity, dimensions, etc). The catheter can be a single-lumen catheteror a multi-lumen catheter. At the catheter's proximal end is a smallorifice 12 b for fluid connection of the catheter to the blood stream.At the catheter's distal end is a connector 18, such as a leur connectoror other fluid connector known in the art.

The illustrations FIGS. 1A to 1E show one exemplary embodiment of theconnector 18 including a flange 18 a and a duct 18 b. In the exemplaryembodiment, the flange 18 a is configured to enable connection of thecatheter to other medical equipment (e.g., saline bag, pressuretransducer, blood chemistry device, and the like) or capping (e.g., witha bung and the like). Although one exemplary connector is shown, oneskilled in the art appreciates a variety of standard or custom madeconnectors suitable for use with the preferred embodiments. The duct 18b is in fluid communication with the catheter lumen and terminates in aconnector orifice 18 c.

In some embodiments, the catheter is inserted into the host's bloodstream, such as into a vein or artery by any useful method known in theart. Generally, prior to and during insertion, the catheter is supportedby a hollow needle or trochar (not shown). For example, the supportedcatheter can be inserted into a peripheral vein or artery, such as inthe host's arm, leg, hand, or foot. Typically, the supporting needle isremoved (e.g., pulled out of the connector) and the catheter isconnected (e.g., via the connector 18) to IV tubing and a saline drip,for example. However, in one embodiment, the catheter is configured tooperatively couple to medical equipment, such as but not limited to asensor system of the preferred embodiments. Additionally and/oralternatively, the catheter can be configured to operatively couple toanother medical device, such as a pressure transducer, for measurementof the host's blood pressure.

In some embodiments, the catheter and the analyte sensor are configuredto indwell within the host's blood stream in vivo. An indwelling medicaldevice, such as a catheter or implant, is disposed within a portion ofthe body for a period of time, from a few minutes or hours to a fewdays, months, or even years. An indwelling catheter is typicallyinserted within a host's vein or artery for a period of time, often 2 ormore days, a month, or even a few months. In some embodiments, thecatheter can indwell in a host's artery or vein for the length of aperioperative period (e.g., the entire hospital stay) or for shorter orlonger periods. In some embodiments, the use of an indwelling catheterpermits continuous access of an analyte sensor to a blood stream whilesimultaneously allowing continuous access to the host's blood stream forother purposes, for example, the administration of therapeutics (e.g.,fluids, drugs, etc.), measurement of physiologic properties (e.g., bloodpressure), fluid removal, and the like.

Referring again to FIGS. 1A to 1E, the system 10 also includes ananalyte sensor 14 configured to extend through the catheter lumen 12 a(see FIG. 1E), out of the catheter orifice 12 b and into the host'sblood stream by about 0.010 inches to about 1 inch, or shorter or longerlengths. In some embodiments, however, the sensor may not extend out ofthe catheter, for example, can reside just inside the catheter tip. Thesensor can extend through the catheter in any functional manner. In someembodiments, the sensor is configured to be held on an inner surface(e.g., the lumen) or outer surface of the catheter, while in otherembodiments, the sensor is configured to “free float” within the lumenof the catheter.

In some embodiments, the sensor 14 is configured to measure theconcentration of an analyte (e.g., glucose, O₂, CO₂, PCO₂, PO₂,potassium, sodium, pH, lactate, urea, bilirubin, creatinine, hematocrit,various minerals, various metabolites, and the like) within the host'sblood stream. Preferably, the sensor includes at least one electrode(see, e.g., FIG. 3B), for example a working electrode; however anycombination of working electrode(s), reference electrode(s), and/orcounter electrode(s) can be implemented as is appreciated by one skilledin the art. Preferably, the sensor 14 includes at least one exposedelectroactive area (e.g., working electrode), a membrane system (e.g.,including an enzyme), a reference electrode (proximal to or remote fromthe working electrode), and an insulator material. Various systems andmethods for design and manufacture of continuous analyte sensors aredescribed in more detail elsewhere herein. In some embodiments, thesensor is a needle-type continuous analyte sensor, configured asdisclosed in U.S. publication US 2006-0020192 and/or U.S. publication US2006-0036143, both of which are incorporated herein by reference intheir entirety. In some embodiments, the sensor is configured to measureglucose concentration. Exemplary sensor configurations are discussed inmore detail, elsewhere herein.

Referring to FIGS. 1A to 1E, the sensor has a proximal end 14 a and adistal end 14 b. At its distal end 14 b, the sensor 14 is associatedwith (e.g., connected to, held by, extends through, and the like) afluid coupler 20 having first and second sides (20 a and 20 b,respectively). The fluid coupler is configured to mate (via its firstside 20 a) to the catheter connector 18. In one embodiment, a skirt 20 cis located at the fluid coupler's first side and includes an interiorsurface 20 d with threads 20 e (see FIGS. 1D and 1E). In thisembodiment, the fluid coupler is configured to mate with the connectorflange 18 a, which is screwed into the fluid coupler via the screwthreads. However, in other embodiments, the fluid coupler is configuredto mate with the connector using any known mating configuration, forexample, a snap-fit, a press-fit, an interference-fit, and the like, andcan include a locking mechanism to prevent separation of the connectorand fluid coupler. The fluid coupler 20 includes a lumen 20 f extendingfrom a first orifice 20 h on its first side 20 a to a second orifice 20i located on the fluid coupler's second side 20 b (FIGS. 1C1 to 1E).When the catheter connector is mated with the fluid coupler, thecatheter's lumen 12 a is in fluid communication with the fluid coupler'slumen 20 f via orifices 18 c and 20 h.

FIGS. 1A to 1D show one embodiment of a fluid coupler 20, namely, aY-coupler; however, any known coupler configuration can be used,including but not limited to a straight coupler, a T-coupler, across-coupler, a custom configured coupler, and the like. In someembodiments, the fluid coupler includes at least one valve (e.g., aseptum, a 3-way valve, a stop-cock valve), which can be used for avariety of purposes (e.g., injection of drugs). The fluid coupler can bemade of any convenient material, such as but not limited to plastic,glass, metal or combinations thereof and can be configured to withstandknown sterilization techniques.

In the exemplary embodiment, the second side 20 b of the fluid coupler20 is configured to be operably connected to IV equipment, anothermedical device or to be capped, and can use any known matingconfiguration, for example, a snap-fit, a press-fit, aninterference-fit, and the like. In one exemplary embodiment, the secondside 20 b is configured to mate with a saline drip, for delivery ofsaline to the host. For example, the saline flows from an elevated bagof sterile saline via tubing, through the fluid coupler, through thecatheter and into the host's blood system (e.g., vein or artery). Inanother embodiment, a syringe can be mated to the fluid coupler, forexample, to withdraw blood from the host, via the catheter. Additionalconnection devices (e.g., a three-way valve) can be operably connectedto the fluid coupler, to support additional functionality and connectionof various devices, such as but not limited to a blood pressuretransducer.

Referring to the exemplary embodiment of FIGS. 1A and 1E, at least aportion of the sensor 14 passes through the fluid coupler 20 (e.g., thefluid coupler lumen 20 f) and is operatively connected to sensorelectronics (not shown) via a hardwire 24. In alternative embodimentshowever, the sensor electronics can be disposed in part or in whole withthe fluid coupler (e.g., integrally with or proximal to) or can bedisposed in part or in whole remotely from the fluid coupler (e.g., on astand or at the bed side). Connections between the sensor and sensorelectronics (in part or in whole) can be accomplished using known wiredor wireless technology. In one exemplary embodiment, the sensor ishardwired to the electronics located substantially wholly remote fromthe fluid coupler (e.g., disposed on a stand or near the bedside); oneadvantage of remote electronics includes enabling a smaller sized fluidcoupler design. In another exemplary embodiment, a portion of the sensorelectronics, such as a potentiostat, is disposed on the fluid couplerand the remaining electronics (e.g., electronics for receiving, dataprocessing, printing, connection to a nurses' station, etc.) aredisposed remotely from the fluid coupler (e.g., on a stand or near thebedside). One advantage of this design can include more reliableelectrical connection with the sensor in some circumstances. In thisembodiment, the potentiostat can be hardwired directly to the remainingelectronics or a transmitter can be disposed on or proximal to the fluidcoupler, for remotely connecting the potentiostat to the remainingelectronics (e.g., by radio frequency (RF)). In another exemplaryembodiment, all of the sensor electronics can be disposed on the fluidcoupler. In still another embodiment, the sensor electronics disposed onthe fluid coupler include a potentiostat.

Referring again to FIGS. 1A to 1E, a protective sheath 26 is configuredto cover at least a portion of the sensor 14 during insertion, andincludes hub 28 and slot 30. In general, the protective sheath protectsand supports the sensor prior to and during insertion into the catheter12 via the connector 18. The protective sheath can be made ofbiocompatible polymers known in the art, such as but not limited topolyethylene (PE), polyurethane (PE), polyvinyl chloride (PVC),polycarbonate (PC), nylon, polyamides, polyimide,polytetrafluoroethylene (PTFE), Teflon, nylon and the like. Theprotective sheath includes a hub 28, for grasping the sheath (e.g.,while maintaining sterilization of the sheath). In this embodiment, thehub additionally provides for mating with the second side 20 b of thefluid coupler 20, prior to and during sensor insertion into thecatheter. In this exemplary embodiment, the slot of the protectivesheath is configured to facilitate release of the sensor therefrom. Inthis embodiment, after the sensor has been inserted into the catheter,the hub is grasped and pulled from the second side of the fluid coupler.This action peels the protective sheath from the sensor (e.g., thesensor slides through the slot as the sheath is removed), leaving thesensor within the catheter. The second side of the fluid coupler can beconnected to other medical devices (e.g., a blood pressure monitor) oran IV drip (e.g., a saline drip), or capped. In alternative embodiments,the sheath can fold (e.g., fold back or concertinas) or retract (e.g.,telescope) during insertion, to expose the sensor. In other embodiments,the sheath can be configured to tear away from the sensor before,during, or after insertion of the sensor. In still other embodiments,the sheath can include an outlet hole 30 a, to allow protrusion of thesensor from the back end of the sheath (e.g., near the hub 28). Oneskilled in the art will recognize that additional configurations can beused, to separate the sensor 14 from the sheath 26.

In some embodiments, the sheath 26 can be optional, depending upon thesensor design. For example, the sensor can be inserted into a catheteror other vascular access device with or without the use of a protectivesheath). In some embodiments, the sensor can be disposed on the outersurface of a catheter (as described elsewhere herein) or on the innersurface of a catheter; and no sheath is provided. In other embodiments,a multi-lumen catheter can be provided with a sensor already disposedwithin one of the lumens; wherein the catheter is inserted into thehost's vein or artery with the sensor already disposed in one of thelumens.

In some alternative embodiments, an analyte sensor is integrally formedon a catheter. In various embodiments, the catheter can be placed into ahost's vein or artery in the usual way a catheter is inserted, as isknown by one skilled in the art, and the host's analyte concentrationmeasured substantially continuously. In some embodiments, the sensorsystem can be coupled to one or more additional devices, such as asaline bag, an automated blood pressure monitor, a blood chemistrymonitor device, and the like. In one exemplary embodiment, theintegrally formed analyte sensor is a glucose sensor.

FIGS. 2A to 2B illustrate one exemplary embodiment of an analyte sensorintegrally formed on a catheter. The system 210 is configured to measurean analyte (e.g., glucose, O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH,lactate, urea, bilirubin, creatinine, hematocrit, various minerals,various metabolites, and the like) and generally includes a catheter 212configured for insertion into a host's blood stream (e.g., via a vein orartery) and a sensor at least partially integrally formed on thecatheter's exterior surface 232. Preferably, the sensor 214 includes atleast one exposed electroactive area 240 (e.g., a working electrode), amembrane system (e.g., including an enzyme), a reference electrode(proximal to or remote from the working electrode), and an insulator.Various systems and methods for design and manufacture of continuousanalyte sensors are described in more detail elsewhere herein.

In this embodiment, the catheter includes a lumen 212 a and an orifice212 b at its proximal end, for providing fluid connection from thecatheter's lumen to the host's blood stream (see FIG. 2A).

In some embodiments, the catheter is inserted into a vein, as describedelsewhere herein. In other embodiments, the catheter is inserted into anartery, as described elsewhere herein. The catheter can be any type ofvenous or arterial catheter commonly used in the art (e.g., peripheralcatheter, central catheter, Swan-Gantz catheter, etc.). The catheter canbe made of any useful medical grade material (e.g., polymers and/orglass) and can be of any size, such as but not limited to from about 1French (0.33 mm) or less to about 30 French (10 mm) or more; forexample, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,or 20 French (3 French is equivalent to about 1 mm). In certainembodiments, the catheter can be a single lumen catheter or amulti-lumen catheter. In some embodiments, the catheter can include oneor more perforations, to allow the passage of host fluid through thelumen of the catheter.

At its distal end 212 c, the catheter 212 includes (e.g., in fluidcommunication) a connector 218. The connector can be of any known type,such as a leur lock, a T-connector, a Y-connector, a cross-connector ora custom configuration, for example. In some embodiments, the connectorincludes at least one valve. At a second side 218 e (e.g., back end),the connector 218 can be operatively connected to a saline system (e.g.,saline bag and tubing), other medical devices (e.g., automatic bloodchemistry machine, dialysis machine, a blood bag for collecting donatedblood, etc.), or capped.

In some embodiments, the system 210 includes sensor electronics (notshown) operatively connected to the analyte sensor, wherein the sensorelectronics are generally configured to measure and/or process thesensor data as described in more detail elsewhere herein. In someembodiments, the sensor electronics can be partially or wholly disposedwith (e.g., integral with, disposed on, or proximal to) the connector218 at the distal end of the catheter or partially or wholly remote fromthe catheter (e.g., on a stand or on the bedside). In one embodiment,the sensor electronics disposed with the connector include apotentiostat. In some embodiments, the sensor electronics are configuredto measure the host's analyte concentration substantially continuously.For example, the sensor can measure the analyte concentrationcontinuously or at time intervals ranging from fractions of a second upto, for example, 1, 2, or 5 minutes or longer.

FIGS. 2C to 2F illustrate additional embodiments of the sensor shown inFIGS. 2A to 2B. The catheter 212 is shown with an integral sensor 214having at least one electrode 240 formed on its exterior surface 232(e.g., FIG. 2F). In general, the sensor can be designed with 1, 2, 3, 4or more electrodes and can be connected by traces (or the like) toelectrical contacts 218 d (or the like) at the second end of theconnector 218 (e.g., FIGS. 2A to 2F). In some embodiments, the sensor ishard-wired to the sensor electronics; alternatively, any operableconnection can be used. Preferably, the sensor includes at least oneworking electrode and at least one reference or counter electrode. Insome embodiments, the reference electrode is located proximal to the atleast one working electrode (e.g., adjacent to or near to the workingelectrode). In some alternative embodiments, the reference electrode islocated remotely from the working electrode (e.g., away from the workingelectrode, such as but not limited to within the lumen of the catheter212 (or connector 218), on the exterior of the sensor system, in contactwith the patient (e.g., on the skin), or the like). In some embodiments,the reference electrode is located proximal to or within the fluidconnector, such as but not limited to coiled about the catheter adjacentto the fluid connector or coiled within the fluid connector and incontact with fluid flowing through the fluid coupler, such as saline orblood. In some embodiments, the sensor can also include one or moreadditional working electrodes (e.g., for measuring baseline, formeasuring a second analyte, or for measuring a substantially non-analyterelated signal, and the like, such as described in more detail inco-pending U.S. Publication No. US-2005-0143635-A1, and U.S. patentapplication Ser. No. 11/543,707 filed on Oct. 4, 2008, U.S. patentapplication Ser. No. 11/543,539 filed on Oct. 4, 2008, U.S. patentapplication Ser. No. 11/543,683 filed on Oct. 4, 2008, and U.S. patentapplication Ser. No. 11/543,734 filed on Oct. 4, 2008, each entitled“DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR,” which areincorporated herein by reference in their entirety. In some embodimentsone or more counter electrodes can be provided on a surface of thecatheter or within or on the fluid connector.

In some of the preferred embodiments, the catheter is designed toindwell within a host's blood flow (e.g., a peripheral vein or artery)and remain in the blood flow for a period of time (e.g., the catheter isnot immediately removed). In some embodiments, the indwelling cathetercan be inserted into the blood flow for example, for a few minutes ormore, between about 1 and 24 hours, between about 1 and 10 days, or evenlonger. For example, the catheter can indwell in the host's blood streamduring an entire perioperative period (e.g., from host admittance,through an operation, and to release from the hospital).

In some embodiments, the catheter is configured as an intravenouscatheter (e.g., configured to be inserted into a vein). The catheter canbe inserted into any commonly used vein, such as in a peripheral vein(e.g., one of the metacarpal veins of the arm); in some embodiments(e.g., such as described with reference to FIGS. 1A to 1E) the analytesensor inserted into a catheter. In alternative embodiments, the sensoris integrally formed on a catheter such as described in more detail withreference to FIGS. 2A to 2F, for example. Other veins, such as leg orfoot veins, hand veins, or even scalp or umbilical veins, can also beused.

In addition to sensing analyte levels via a sensor system as describedherein, the intravenous catheter can be used for delivery of fluidsand/or drugs to the host's circulatory system. The catheter can beconfigured to be coupled to other medical devices or functions, forexample, saline, blood products, total parenteral feeding or medicationscan be given to the host via the indwelling intravenous catheter. Insome embodiments, the catheter can be operatively connected to a pump,such as an infusion pump, to facilitate flow of the fluids into the hostand a desired rate. For example, an infusion pump can pump saline intothe host at a rate of 1 cc per minute, or at higher or lower rates. Therate of infusion can be changed (increased or decreased). For example,an infusion can be temporarily stopped, to permit injection of painmedication into the IV system, followed by increasing the infusion rate(e.g., for 5 minutes) to rapidly deliver the pain medication to thehost's circulatory system.

In some embodiments, the catheter is configured as an arterial catheter(e.g., configured to be inserted into an arterial line or as part of anarterial line). Typically, an arterial catheter is inserted in the wrist(radial artery), armpit (axillary artery), groin (femoral artery), orfoot (pedal artery). Generally, arterial catheters provide access to thehost's blood stream (arterial side) for removal of blood samples and/orapplication of test devices, such as but not limited to a pressuretransducer (for measuring blood pressure automatically), however,arterial catheters can also be used for delivery of fluids ormedications. In one embodiment, a catheter is inserted into an arterialline and the sensor inserted into the catheter (e.g., functionallycoupled) as described elsewhere herein. Saline filled non-compressibletubing is then coupled to the sensor, followed by a pressure transducer.An automatic flushing system (e.g., saline) is coupled to the tubing aswell as a pressure bag to provide the necessary pressure. Electronicsare generally operatively coupled to the pressure transducer forcalculating and displaying a variety of parameters including bloodpressure. Other medical devices can also be connected to the arterialcatheter, to measure various blood components, such as but not limitedto O₂, CO₂, PCO₂, PO₂, potassium, sodium, pH, lactate, urea, bilirubin,creatinine, hematocrit, various minerals, various metabolites, and thelike.

In another embodiment, a blood pressure measurement system is insertedinto the host and can be used as is known in the art. The analyte sensor(e.g., glucose sensor), such as the embodiment shown in FIGS. 1A-1E, isinserted into the pre-inserted (e.g., already in-dwelling) catheterusing the following general methodology. First, the pressure transduceris temporarily disabled by disconnecting from the pre-inserted catheter.A cap (optionally) covers the protective slotted sheath and can beremoved so as to enable the sensor to be grasped at the fluid coupler.The sheath, which is generally more rigid than the sensor but lessflexible than a needle, is then threaded through the pre-insertedcatheter so as to extend beyond the catheter into the blood stream(e.g., by about 0.001 inches to about 1 inches). The sheath is thenremoved by sliding the sensor through a small outlet hole and/or slot inthe sheath. Thus, the sensor remains within the pre-inserted catheterand the fluid coupler, which supports the distal portion of the sensor,is coupled to the catheter itself. Saline filled non-compressible tubingis then coupled to the second side (e.g., back end) of the fluidcoupler. The sensor electronics (whether adjacent to the fluid coupleror otherwise wired to the fluid coupler) are then operatively connected(e.g., wired or wirelessly) to the sensor to initiate sensor function.

In some embodiments, a portion of the sensor system (e.g., sensor,catheter, or other component) can be configured to allow removal ofblood samples from the host's blood stream (e.g., artery or vein).Sample removal can be done using any systems and methods known in theart, for example, as is practiced for removing a blood sample from anarterial catheter (e.g., and arterial line). In one such exemplaryembodiment, any tubing or equipment coupled to the second side of thefluid coupler is disconnected. A syringe is then be coupled to thesecond side and blood removed via the catheter by pulling back on thesyringe plunger. In a further embodiment, saline can be flushed throughthe fluid coupler and catheter. In another embodiment, the fluid couplercan be configured with a side valve, to allow coupling of a syringe, forremoval of blood samples or delivery of fluids, such as medications,without disconnecting attached tubing of equipment, and the like. Instill another embodiment, a valve or diaphragm, for access to the systemby a syringe, can be coupled into the tubing at a short distance fromthe fluid coupler. In yet another embodiment, the sensor is integrallyformed on the arterial catheter, such as the embodiment shown in FIGS.2A-2B, and tubing can be disconnected from the connector, a syringeoperably associated with the connector, and blood removed with thesyringe. After blood collection, the syringe is removed and the tubingreconnected to the connector.

In still another embodiment, the analyte sensor can be functionallycoupled to an extracorporeal blood flow device. A variety of devicesexist for testing various blood properties/analytes at the bedside, suchas but not limited to the blood gas and chemistry devices manufacturedby Via Medical, Austin, Tex., USA. These devices generally withdraw ablood sample from the host, test the blood sample, and then return it tothe host. Such a device can be connected in series to the arterialcatheter, with the sensor in-between, and using systems and methodsknown in the art. In one embodiment, a sensor, such as the embodimentshown in FIGS. 1A-1E, is functionally connected to an in-dwellingarterial catheter, as described herein, and the extracorporeal bloodflow device is connected to the second side of the fluid coupler. In analternative embodiment, the sensor is integrally formed on the arterialcatheter, such as the embodiment shown in FIGS. 2A-2F, and theextracorporeal blood flow device is functionally connected to theconnector 218. Other devices, such as but not limited to dialysismachines, heart-lung bypass machines or blood collection bags, or othervascular access devices, can be functionally coupled to the analytesensor.

The analyte sensor system of the preferred embodiments can be designedwith a variety of alternative configurations. In some embodiments, thesensor is connected to a fluid connection device. The fluid connectiondevice in these embodiments can be any standard fluid connection deviceknown in the art, such as a fluid coupler, or a fluid coupler custommanufactured to preferred specifications. On its first side, the fluidcoupler is configured to couple to an existing catheter or cannula (asdescribed with reference to FIGS. 1A-1E). The catheter (or cannula) istypically inserted into a vascular access device and/or into a hospitalhost during a hospital stay. For example, the catheter can be insertedinto an arterial line (e.g., for removing blood samples or for measuringblood pressure using a pressure transducer) or a venous line (e.g., forintravenous delivery of drugs and other fluids). In general practice,the catheter is inserted into the host's blood vessel, for example, andmaintained there for a period of time during the host's hospital stay,such as part of the stay or during the entire stay (e.g.,perioperatively). In one alternative embodiment, another vascular accessdevice (e.g., other than a catheter) can be used to receive the sensor.In yet another alternative embodiment, the sensor system of thepreferred embodiments can be inserted into a vascular access device(e.g., rather than the vascular system directly). Some examples ofvascular access devices include but are not limited to, catheters,shunts, automated blood withdrawal devices and the like.

In some embodiments, such as the embodiment illustrated in FIGS. 1A to1E, the system 10 is configured such that the sensor is inserted into avascular access device, such as but not limited to a catheter 12 (e.g.,a catheter that has been inserted into the host's blood stream prior tosensor insertion). In general, catheters are small, flexible tubes(e.g., soft catheter) but they can also be larger, rigid tubes.Catheters are inserted into a host's body cavity, vessel, or duct toprovide access for fluid removal or insertion, or for access to medicalequipment. Catheters can also be inserted into extracorporeal devices,such as but not limed to an arterio-venous shunt for the transfer ofblood from an artery to a vein. Some catheters are used to direct accessto the circulatory system (e.g., venous or arterial catheters, SwanGantz catheters) to allow removal of blood samples, the infusion offluids (e.g., saline, medications, blood or total parenteral feeding) oraccess by medical devices (e.g., stents, extracorporeal blood chemistryanalysis devices, invasive blood pressure monitors, etc.).

Preferably, the sensor is designed to include a protective cap, asillustrated in FIGS. 1A-1E. Namely, FIGS. 1A and 1B illustrates thecatheter (the catheter cap having been removed prior to insertion), wellknown to those skilled in the art, which can be inserted into the host'sblood vessel using standard methods. The sensor 14 is configured formeasurement of an analyte (e.g., glucose) in the host's body, and is influid connection within the catheter lumen, which is in fluid connectionwith the fluid coupler 20 of the sensor. The first side 20 a of thefluid coupler 20 of the sensor is designed to couple to the catheter,e.g., by screwing or snapping thereon, and can also couple (on itssecond side 20 b) with other medical devices. One advantage of the fluidcoupler is that it provides for a small amount of bleed back, to preventair bubbles in the host's blood stream.

The exemplary sensor system 10 of FIGS. 1A and 1B further includes aslotted protective sheath 26 that supports and protects the sensorduring sensor insertion, for example, the sheath increases the sensorvisibility (e.g., the sensor is so thin that it can be difficult forsome people to see without the protective sheath) and provides for easeof sliding the sensor into the catheter. The slotted protective sheathis configured to fit within the fluid coupler and houses the sensorduring insertion of the sensor into the catheter (e.g., an indwellingcatheter within the host's blood flow). Preferably, the protectivesheath is substantially more rigid than the sensor and at the same timesubstantially more flexible that a standard syringe needle, howeverother designs are possible. To facilitate removal of the protectivesheath, a slot 30 is provided with an optional outlet hole 30 a, whichis described in more detail with reference to FIG. 1C, and a hub 28. Bygrasping and pulling the hub, the user (e.g., health care professional)can withdraw the protective sheath after coupling the fluid coupler tothe catheter. Prior to insertion of the sensor, a cap is provided, tocover the protective sheath, for example, to keep the sheath and sensorsterile, and to prevent damage to the components during shipping and/orhandling.

In general, the sensor system is configured with a potentiostat and/orsensor electronics that are operatively coupled to the sensor. In someembodiments, a portion of the sensor electronics, such as thepotentiostat, can be disposed directly on the fluid coupler. However,some or all of the sensor electronics (including the potentiostat) canbe disposed remotely from the fluid coupler (e.g., on the bedside or ona stand) and can be functionally coupled (e.g., wired or wireless), asis generally known to those skilled in the art.

FIGS. 1C1 and 1C2 are cross-sectional views (not to scale) of the fluidcoupler, including a protective sheath 26, a sensor 14, and a cap 32(cap to be removed prior to insertion) in one embodiment. The protectivesheath 26 extends through the fluid coupler and houses the sensor, forsensor insertion into a catheter. The protective sheath includes anoptional outlet hole 30 a, through which the sensor extends and a slot30 along a length of the protective sheath that communicates with theoutlet hole and enables the protective sheath to be removed after thesensor has been inserted into the host's body. The protective sheathincludes a hub 28 for ease of handling.

In some embodiments, the glucose sensor is utilized in combination withanother medical device (e.g., a medical device or access port that isalready coupled to, applied to, or connected to the host) in a hospitalor similar clinical setting. For example, a catheter can be insertedinto the host's vein or artery, wherein the catheter can is connected toadditional medical equipment. In an alternative example, the catheter isplaced in the host to provide quick access to the host's circulatorysystem (in the event of a need arising) and is simply capped. In anotherexample, a dialysis machine can be connected to the host's circulatorysystem. In another example, a central line can be connected to the host,for insertion of medical equipment at the heart (e.g., the medicalequipment reaches the heart through the vascular system, from aperipheral location such as a leg or arm pit).

In practice of coupling to a catheter, before insertion of the sensor,the access port is opened. In one exemplary embodiment of a pre-insertedcatheter that is capped, the cap is removed and the sensor inserted intothe catheter. The back end of the sensor system can be capped orattached to additional medical equipment (e.g., saline drip, bloodpressure transducer, dialysis machine, blood chemistry analysis device,etc.). In another exemplary embodiment, medical equipment (e.g., salinedrip, blood pressure transducer, dialysis machine, blood chemistryanalysis device, etc.) is already connected to the catheter. The medicalequipment is disconnected from the catheter, the sensor inserted into(and coupled to) the catheter and then the medical equipment reconnected(e.g., coupled to the back end of the sensor system).

In some embodiments, the sensor is inserted directly into the host'scirculatory system without a catheter or other medical device. In onesuch exemplary embodiment, the sheath covering the sensor is relativelyrigid and supports the sensor during insertion. After the sensor hasbeen inserted into the host's vein or artery, the supportive sheath isremoved, leaving the exposed sensor in the host's vein or artery. In analternative example, the sensor is inserted into a vascular accessdevice (e.g., with or without a catheter) and the sheath removed, toleave the sensor in the host's vein or artery (e.g., through thevascular access device).

In various embodiments, in practice, prior to insertion, the cap 32 overthe protective sheath is removed as the health care professional holdsthe glucose sensor by the fluid coupler 20. The protective sheath 26,which is generally more rigid than the sensor but more flexible than aneedle, is then threaded through the catheter so as to extend beyond thecatheter into the blood flow (e.g., by about 0.010 inches to about 1inches). The protective sheath is then removed by sliding the sensorthrough the (optional) outlet hole 30 a and slotted portion 30 of thesheath (e.g., by withdrawing the protective sheath by pulling the hub28). Thus the sensor remains within the catheter; and the fluid coupler20, which holds the sensor 14, is coupled to the catheter itself (viaits connector 18). Other medical devices can be coupled to the secondside of the fluid coupler as desired. The sensor electronics (e.g.,adjacent to the fluid coupler or otherwise coupled to the fluid coupler)are then operatively connected (e.g., wired or wirelessly) to the sensorfor proper sensor function as is known in the art.

In another embodiment, the catheter 12 includes a plurality ofperforations (e.g., holes) that allow the host's fluid (e.g., blood) toflow through the lumen 12 a of the catheter. The fluid flowing throughthe catheter can make contact with a sensor 14 inserted therein. In afurther embodiment, the sensor does not protrude out of the catheter'stip 12 b and the host's blood flowing through the perforated catheter'slumen contacts the sensor's electroactive surfaces.

In still another embodiment, the catheter 12 includes at least a firstlumen and a second lumen. The sensor 14 is configured for insertion intothe catheter's first lumen. The second lumen can be used for infusionsinto the host's circulatory system or sample removal without disturbingthe sensor within the first lumen.

FIGS. 2A-2F are schematic views of a sensor integrally formed(integrally incorporated) onto a surface of a catheter, in someexemplary embodiments. In some embodiments, the sensor can be integrallyformed on an exterior surface 232 of the catheter. In other embodiments,the sensor can be integrally formed on an interior surface of thecatheter (e.g., on a lumenal surface). In still other embodiments, thesensor can be integrally formed on the sensor's tip (e.g., as indicatedby 214 a). In yet other embodiments, the sensor can be integrallyincorporated with the catheter, for example by bonding a sensor of thetype described in FIGS. 3A to 3C into an inner or outer surface of thecatheter.

Generally, the sensor system is provided with a cap that covers thecatheter and in vivo portion of the integral sensor. A needle or trocharthat runs the length of the catheter supports the device duringinsertion into the host's blood stream. Prior to use, medical caregiverholds the device by the fluid connector 218 and removes the cap toexpose the in vivo portion of the device (e.g., the catheter). Thecaregiver inserts the in vivo portion of the device into one of thehost's veins or arteries (depending upon whether the catheter is anintravenous catheter or an arterial catheter). After insertion, theneedle is withdrawn from the device. The device is then capped orconnected to other medical equipment (e.g., saline bag, pressuretransducer, blood collection bag, total parenteral feeding, dialysisequipment, automated blood chemistry equipment, etc.). In somealternative embodiments, the sensor-integrated catheter can be incommunication (e.g., fluid communication) with the host's vascularsystem through a vascular access device.

In some embodiments, a glucose sensor system includes a sensingmechanism substantially similar to that described in U.S. Publication2006-0020187, which is incorporated herein by reference in its entirety;for example, with platinum working electrode and silver referenceelectrode coiled there around. Alternatively, the reference electrodecan be located remote from the working electrode so as not to beinserted into the host, and can be located, for example, within thefluid coupler, thereby allowing a smaller footprint in the portion ofthe sensor adapted for insertion into the body (e.g., blood stream); forexample, without a coiled or otherwise configured reference electrodeproximal to the working electrode. Although a platinum working electrodeis discussed, a variety of known working electrode materials can beutilized (e.g., Platinum-Iridium or Iridium). When located remotely, thereference electrode can be located away from the working electrode(e.g., the electroactive portion) at any location and with anyconfiguration so as to maintain bodily and/or in fluid communicationtherewith as is appreciated by one skilled in the art.

In an alternative embodiment, the sensor tip 14 a includes an enlarged,atraumatic area, for example a dull or bulbous portion about two timesthe diameter of the sensor or larger. In one exemplary embodiment, theenlarged portion is created by heating, welding, crushing or bonding asubstantially rounded structure onto the tip of the sensor (e.g.,polymer or metal). In another exemplary embodiment, the tip of thesensor is heated (e.g., arc welded or flash-butt resistance welded) tocause the tip to enlarge (e.g., by melting). The enlarged portion can beof any atraumatic shape, such as but not limited to oval, round,cone-shaped, cylindrical, teardrop, etc. While not wishing to be boundby theory, it is believed that an atraumatic or enlarged area enablesenhanced stability of a small diameter sensor in the blood flow andensures that the sensor remains within the blood flow (e.g., to avoidpiercing a vessel wall and/or becoming inserted subluminally.)

In some embodiments, a second working electrode can be provided on thesensor for measuring baseline, and thereby subtracting the baseline fromthe first working electrode to obtain a glucose-only signal, asdisclosed in copending U.S. Publication No. US-2005-0143635-A1, and U.S.patent application Ser. No. 11/543,707 filed on Oct. 4, 2008, U.S.patent application Ser. No. 11/543,539 filed on Oct. 4, 2008, U.S.patent application Ser. No. 11/543,683 filed on Oct. 4, 2008, and U.S.patent application Ser. No. 11/543,734 filed on Oct. 4, 2008, eachentitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR,” hereinincorporated by reference in its entirety.

Referring now to FIGS. 2A-2E in more detail, some embodiments of theanalyte sensor system include a catheter 212 adapted for inserting intoa host in a hospital or clinical setting, wherein the analyte sensor 214is built integrally with the catheter 212. For example, a glucose sensorcan be integrally formed on the catheter itself. FIGS. 2A-2B illustrateone embodiment, wherein the catheter 212 is configured both forinsertion into a host, and can be configured to couple to other medicaldevices on its ex vivo end. However, coupling to other medical devicesis not necessary. In some embodiments, the catheter includes a connector218 configured for connection to tubing or other medical devices, asdescribed herein. The embodiment shown in FIGS. 2A-2B includes two orthree electrodes 240 on the outer surface of the in vivo portion of thecatheter 212. In some embodiments, the catheter is perforated (asdescribed elsewhere herein) and at least one electrode is disposedwithin the lumen (not shown) of the perforated catheter. In someembodiments, the catheter includes a single lumen. In other embodiment,the catheter includes two or more lumens.

With reference to FIGS. 2C-2E, in some embodiments, at least one workingelectrode 240 is disposed on the exterior surface of the in vivo portionof the catheter. Alternatively, the at least one working electrode canbe disposed on an interior surface of the catheter, the tip of thecatheter, extend from the catheter, and the like. In general, thepreferred embodiments can be designed with any number of electrodes,including one or more counter electrodes, one or more referenceelectrodes, and/or one or more auxiliary working electrodes. In furtherembodiments, the electrodes can be of relatively larger or smallersurface area, depending upon their uses. In one example, a sensorincludes a working electrode and a reference electrode that has a largersurface area (relative to the surface area of the working electrode) onthe surface of the catheter. In another example, a sensor includes aworking electrode, a counter electrode, and a reference electrode sizedto have an increased surface area as compared to the working and/orcounter electrode. In some embodiments, the reference electrode isdisposed at a location remote from the working electrode, such as withinthe connector (e.g., coiled within the connector). In some embodiments,the reference electrode is located on the host's body (e.g., in bodycontact).

The electrodes 240 can be deposited on the catheter using any suitabletechniques known in the art, for example, thick or thin film depositiontechniques. The electrodes can be formed of any advantageous electrodematerials known in the art (e.g., platinum, platinum-iridium, palladium,graphite, gold, carbon, silver, silver-silver chloride, conductivepolymer, alloys, combinations thereof, and the like). In otherembodiments, one or more of the electrodes is formed from anelectrically conductive material (e.g., wire or foil comprisingplatinum, platinum-iridium, palladium, graphite, gold, carbon, silver,silver-silver chloride, conductive polymer, alloys, combinationsthereof, and the like) applied to the exterior surface of the catheter,such as but not limited twisting, coiling, rolling or adhering.

In some embodiments, the catheter is (wired or wirelessly) connected tosensor electronics (not shown, disposed on the catheter's connectorand/or remote from the catheter) so as to electrically connect theelectrodes on the catheter with the sensor electronics. The insertedcatheter (including the sensor integrally formed thereon) can beutilized by other medical devices for a variety of functions (e.g.,blood pressure monitor, drug delivery, etc).

While not wishing to be bound by theory, a number of the systems andmethods disclosed in the preferred embodiments (e.g., an analyte sensorto be disposed in communication with the host's blood), can be employedin transcutaneous (e.g., transdermal) or wholly implantable analytesensor devices. For example, the sensor could be integrally formed onthe in vivo portion of a subcutaneous device or a wholly implantabledevice. As another example, an enlarged surface area (e.g., bulbous end)can useful in the design of a transcutaneous analyte sensor.

Exemplary Sensor Configurations

Referring to FIGS. 3A to 3C, in some embodiments, the sensor can beconfigured similarly to the continuous analyte sensors disclosed inco-pending U.S. patent application Ser. No. 11/360,250 filed Feb. 22,2006 and entitled “ANALYTE SENSOR,” herein incorporated by reference inits entirety. The sensor includes a distal portion 342, also referred toas the in vivo portion, adapted for insertion into the catheter asdescribed above, and a proximal portion 340, also referred to as an exvivo portion, adapted to operably connect to the sensor electronics.Preferably, the sensor includes two or more electrodes: a workingelectrode 344 and at least one additional electrode, which can functionas a counter electrode and/or reference electrode, hereinafter referredto as the reference electrode 346. A membrane system is preferablydeposited over the electrodes, such as described in more detail withreference to FIGS. 3A to 3C, below.

FIG. 3B is an expanded cutaway view of a distal portion of the sensor inone embodiment, showing working and reference electrodes. In preferredembodiments, the sensor is formed from a working electrode 344 (e.g., awire) and a reference electrode 346 helically wound around the workingelectrode 344. An insulator 345 is disposed between the working andreference electrodes to provide electrical insulation therebetween.Certain portions of the electrodes are exposed to enable electrochemicalreaction thereon, for example, a window 343 can be formed in theinsulator to expose a portion of the working electrode 344 forelectrochemical reaction.

In preferred embodiments, each electrode is formed from a fine wire witha diameter of from about 0.001 inches or less to about 0.010 inches ormore, for example, and is formed from, e.g., a plated insulator, aplated wire, or bulk electrically conductive material. Although theillustrated electrode configuration and associated text describe onepreferred method of forming a sensor, a variety of known sensorconfigurations can be employed with the analyte sensor system of thepreferred embodiments, such as U.S. Pat. No. 5,711,861 to Ward et al.,U.S. Pat. No. 6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Sayet al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718to Heller, U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No.6,214,185 to Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunninghamet al., and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No.6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al.,U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No. 6,424,847 toMastrototaro et al., U.S. Pat. No. 6,424,847 to Mastrototaro et al, forexample. All of the above patents are incorporated in their entiretyherein by reference and are not inclusive of all applicable analytesensors; in general, it should be understood that the disclosedembodiments are applicable to a variety of analyte sensorconfigurations. It is noted that much of the description of thepreferred embodiments, for example the membrane system described below,can be implemented not only with in vivo sensors, but also with in vitrosensors, such as blood glucose meters (SMBG).

In some embodiments, the working electrode comprises a wire formed froma conductive material, such as platinum, platinum-iridium, palladium,graphite, gold, carbon, conductive polymer, alloys, and the like.Although the electrodes can by formed by a variety of manufacturingtechniques (bulk metal processing, deposition of metal onto a substrate,and the like), it can be advantageous to form the electrodes from platedwire (e.g., platinum on steel wire) or bulk metal (e.g., platinum wire).It is believed that electrodes formed from bulk metal wire providesuperior performance (e.g., in contrast to deposited electrodes),including increased stability of assay, simplified manufacturability,resistance to contamination (e.g., which can be introduced in depositionprocesses), and improved surface reaction (e.g., due to purity ofmaterial) without peeling or delamination.

In some embodiments, the working electrode is formed of platinum-iridiumor iridium wire. In general, platinum-iridium and iridium materials aregenerally stronger (e.g., more resilient and less likely to fail due tostress or strain fracture or fatigue). It is believed thatplatinum-iridium and/or iridium materials can facilitate a wire with asmaller diameter to further decrease the maximum diameter (size) of thesensor (e.g., in vivo portion). Advantageously, a smaller sensordiameter both reduces the risk of clot or thrombus formation (or otherforeign body response) and allows the use of smaller catheters.

The electroactive window 343 of the working electrode 344 is configuredto measure the concentration of an analyte. In an enzymaticelectrochemical sensor for detecting glucose, for example, the workingelectrode measures the hydrogen peroxide produced by an enzyme catalyzedreaction of the analyte being detected and creates a measurableelectronic current For example, in the detection of glucose whereinglucose oxidase produces hydrogen peroxide as a byproduct, hydrogenperoxide reacts with the surface of the working electrode producing twoprotons (2H⁺), two electrons (2e⁻) and one molecule of oxygen (O₂),which produces the electronic current being detected.

In preferred embodiments, the working electrode 344 is covered with aninsulating material 345, for example, a non-conductive polymer.Dip-coating, spray-coating, vapor-deposition, or other coating ordeposition techniques can be used to deposit the insulating material onthe working electrode. In one embodiment, the insulating materialcomprises parylene, which can be an advantageous polymer coating for itsstrength, lubricity, and electrical insulation properties. Generally,parylene is produced by vapor deposition and polymerization ofpara-xylylene (or its substituted derivatives). While not wishing to bebound by theory, it is believed that the lubricious (e.g., smooth)coating (e.g., parylene) on the sensors of some embodiments contributesto minimal trauma and extended sensor life. While parylene coatings aregenerally preferred in some embodiments, any suitable insulatingmaterial can be used, for example, fluorinated polymers,polyethyleneterephthalate, polyurethane, polyimide, other nonconductingpolymers, and the like. Glass or ceramic materials can also be employed.Other materials suitable for use include surface energy modified coatingsystems such as are marketed under the trade names AMC18, AMC148,AMC141, and AMC321 by Advanced Materials Components Express ofBellafonte, Pa. In some alternative embodiments, however, the workingelectrode may not require a coating of insulator.

The reference electrode 346, which can function as a reference electrodealone, or as a dual reference and counter electrode, is formed fromsilver, silver/silver chloride, and the like. In some embodiments, thereference electrode 346 is juxtapositioned and/or twisted with or aroundthe working electrode 344; however other configurations are alsopossible (e.g., coiled within the fluid connector, or an intradermal oron-skin reference electrode). In the illustrated embodiments, thereference electrode 346 is helically wound around the working electrode344. The assembly of wires is then optionally coated or adhered togetherwith an insulating material, similar to that described above, so as toprovide an insulating attachment.

In some embodiments, a silver wire is formed onto the sensor asdescribed above, and subsequently chloridized to form silver/silverchloride reference electrode. Advantageously, chloridizing the silverwire as described herein enables the manufacture of a referenceelectrode with optimal in vivo performance. Namely, by controlling thequantity and amount of chloridization of the silver to formsilver/silver chloride, improved break-in time, stability of thereference electrode, and extended life has been shown with someembodiments. Additionally, use of silver chloride as described aboveallows for relatively inexpensive and simple manufacture of thereference electrode.

In embodiments wherein an outer insulator is disposed, a portion of thecoated assembly structure can be stripped or otherwise removed, forexample, by hand, excimer lasing, chemical etching, laser ablation,grit-blasting (e.g., with sodium bicarbonate or other suitable grit),and the like, to expose the electroactive surfaces. Alternatively, aportion of the electrode can be masked prior to depositing the insulatorin order to maintain an exposed electroactive surface area. In oneexemplary embodiment, grit blasting is implemented to expose theelectroactive surfaces, preferably utilizing a grit material that issufficiently hard to ablate the polymer material, while beingsufficiently soft so as to minimize or avoid damage to the underlyingmetal electrode (e.g., a platinum electrode). Although a variety of“grit” materials can be used (e.g., sand, talc, walnut shell, groundplastic, sea salt, and the like), in some preferred embodiments, sodiumbicarbonate is an advantageous grit-material because it is sufficientlyhard to ablate, e.g., a parylene coating, without damaging, e.g., anunderlying platinum conductor. One additional advantage of sodiumbicarbonate blasting includes its polishing action on the metal as itstrips the polymer layer, thereby eliminating a cleaning step that mightotherwise be necessary.

In the embodiment illustrated in FIG. 3B, a radial window 343 is formedthrough the insulating material 345 to expose a circumferentialelectroactive surface of the working electrode. Additionally, sectionsof electroactive surface of the reference electrode are exposed. Forexample, the sections of electroactive surface can be masked duringdeposition of an outer insulating layer or etched after deposition of anouter insulating layer.

In some applications, cellular attack or migration of cells to thesensor can cause reduced sensitivity and/or function of the device,particularly after the first day of implantation. However, when theexposed electroactive surface is distributed circumferentially about thesensor (e.g., as in a radial window), the available surface area forreaction can be sufficiently distributed so as to minimize the effect oflocal cellular invasion of the sensor on the sensor signal.Alternatively, a tangential exposed electroactive window can be formed,for example, by stripping only one side of the coated assemblystructure. In other alternative embodiments, the window can be providedat the tip of the coated assembly structure such that the electroactivesurfaces are exposed at the tip of the sensor. Other methods andconfigurations for exposing electroactive surfaces can also be employed.

In some embodiments, the working electrode has a diameter of from about0.001 inches or less to about 0.010 inches or more, preferably fromabout 0.002 inches to about 0.008 inches, and more preferably from about0.004 inches to about 0.005 inches. The length of the window can be fromabout 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078inches) or more, and preferably from about 0.25 mm (about 0.01 inches)to about 0.375 mm (about 0.015 inches). In such embodiments, the exposedsurface area of the working electrode is preferably from about 0.000013in² (0.0000839 cm²) or less to about 0.0025 in² (0.016129 cm²) or more(assuming a diameter of from about 0.001 inches to about 0.010 inchesand a length of from about 0.004 inches to about 0.078 inches). Thepreferred exposed surface area of the working electrode is selected toproduce an analyte signal with a current in the picoAmp range, such asis described in more detail elsewhere herein. However, a current in thepicoAmp range can be dependent upon a variety of factors, for examplethe electronic circuitry design (e.g., sample rate, current draw, A/Dconverter bit resolution, etc.), the membrane system (e.g., permeabilityof the analyte through the membrane system), and the exposed surfacearea of the working electrode. Accordingly, the exposed electroactiveworking electrode surface area can be selected to have a value greaterthan or less than the above-described ranges taking into considerationalterations in the membrane system and/or electronic circuitry. Inpreferred embodiments of a glucose sensor, it can be advantageous tominimize the surface area of the working electrode while maximizing thediffusivity of glucose in order to optimize the signal-to-noise ratiowhile maintaining sensor performance in both high and low glucoseconcentration ranges.

In some alternative embodiments, the exposed surface area of the working(and/or other) electrode can be increased by altering the cross-sectionof the electrode itself. For example, in some embodiments thecross-section of the working electrode can be defined by a cross, star,cloverleaf, ribbed, dimpled, ridged, irregular, or other non-circularconfiguration; thus, for any predetermined length of electrode, aspecific increased surface area can be achieved (as compared to the areaachieved by a circular cross-section). Increasing the surface area ofthe working electrode can be advantageous in providing an increasedsignal responsive to the analyte concentration, which in turn can behelpful in improving the signal-to-noise ratio, for example.

In some alternative embodiments, additional electrodes can be includedwithin the assembly, for example, a three-electrode system (working,reference, and counter electrodes) and/or an additional workingelectrode (e.g., an electrode which can be used to generate oxygen,which is configured as a baseline subtracting electrode, or which isconfigured for measuring additional analytes). U.S. Publication No.US-2005-0161346-A1, U.S. Publication No. US-2005-0143635-A1, and U.S.patent application Ser. No. 11/543,707 filed on Oct. 4, 2008, U.S.patent application Ser. No. 11/543,539 filed on Oct. 4, 2008, U.S.patent application Ser. No. 11/543,683 filed on Oct. 4, 2008, and U.S.patent application Ser. No. 11/543,734 filed on Oct. 4, 2008, eachentitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR,”describe some systems and methods for implementing and using additionalworking, counter, and/or reference electrodes. In one implementationwherein the sensor comprises two working electrodes, the two workingelectrodes are juxtapositioned (e.g., extend parallel to each other),around which the reference electrode is disposed (e.g., helicallywound). In some embodiments wherein two or more working electrodes areprovided, the working electrodes can be formed in a double-, triple-,quad-, etc. helix configuration along the length of the sensor (forexample, surrounding a reference electrode, insulated rod, or othersupport structure). The resulting electrode system can be configuredwith an appropriate membrane system, wherein the first working electrodeis configured to measure a first signal comprising glucose and baseline(e.g., background noise) and the additional working electrode isconfigured to measure a baseline signal consisting of baseline only(e.g., configured to be substantially similar to the first workingelectrode without an enzyme disposed thereon). In this way, the baselinesignal can be subtracted from the first signal to produce a glucose-onlysignal that is substantially not subject to fluctuations in the baselineand/or interfering species on the signal.

Although the embodiments of FIGS. 3A to 3C illustrate one electrodeconfiguration including one bulk metal wire helically wound aroundanother bulk metal wire, other electrode configurations are alsocontemplated. In an alternative embodiment, the working electrodecomprises a tube with a reference electrode disposed or coiled inside,including an insulator therebetween. Alternatively, the referenceelectrode comprises a tube with a working electrode disposed or coiledinside, including an insulator therebetween. In another alternativeembodiment, a polymer (e.g., insulating) rod is provided, wherein theelectrodes are deposited (e.g., electro-plated) thereon. In yet anotheralternative embodiment, a metallic (e.g., steel) rod is provided, coatedwith an insulating material, onto which the working and referenceelectrodes are deposited. In yet another alternative embodiment, one ormore working electrodes are helically wound around a referenceelectrode.

Preferably, the electrodes and membrane systems of the preferredembodiments are coaxially formed, namely, the electrodes and/or membranesystem all share the same central axis. While not wishing to be bound bytheory, it is believed that a coaxial design of the sensor enables asymmetrical design without a preferred bend radius. Namely, in contrastto prior art sensors comprising a substantially planar configurationthat can suffer from regular bending about the plane of the sensor, thecoaxial design of the preferred embodiments do not have a preferred bendradius and therefore are not subject to regular bending about aparticular plane (which can cause fatigue failures and the like).However, non-coaxial sensors can be implemented with the sensor systemof the preferred embodiments.

In addition to the above-described advantages, the coaxial sensor designof the preferred embodiments enables the diameter of the connecting endof the sensor (proximal portion) to be substantially the same as that ofthe sensing end (distal portion) such that the protective slotted sheathis able to insert the sensor into the catheter and subsequently slideback over the sensor and release the sensor from the protective slottedsheath, without complex multi-component designs.

In one such alternative embodiment, the two wires of the sensor are heldapart and configured for insertion into the catheter in proximal butseparate locations. The separation of the working and referenceelectrodes in such an embodiment can provide additional electrochemicalstability with simplified manufacture and electrical connectivity. Oneskilled in the art will appreciate that a variety of electrodeconfigurations can be implemented with the preferred embodiments.

In addition to the above-described configurations, the referenceelectrode can be separated from the working electrode, and coiled withina portion of the fluid connector, in some embodiments. In anotherembodiment, the reference electrode is coiled within the fluid connectorand adjacent to its first side. In an alternative embodiment, thereference electrode is coiled within the fluid connector and adjacent toits second side. In such embodiments, the reference electrode is incontact with fluid, such as saline from a saline drip that is flowinginto the host, or such as blood that is being withdrawn from the host.While not wishing to be bound by theory, this configuration is believedto be advantageous because the sensor is thinner, allowing the use ofsmaller catheters and/or a reduced likelihood to thrombus production.

In another embodiment, the reference electrode 346 can be disposedfarther away from the electroactive portion of the working electrode 343(e.g., closer to the fluid connector). In some embodiments, thereference electrode is located proximal to or within the fluid coupler,such as but not limited to coiled about the catheter adjacent to thefluid coupler or coiled within the fluid coupler and in contact withfluid flowing through the fluid coupler, such as saline. Theseconfigurations can also minimize at least a portion of the sensordiameter and thereby allow the use of smaller catheters and reduce therisk of clots.

In addition to the embodiments described above, the sensor can beconfigured with additional working electrodes as described in U.S.Publication No. US-2005-0143635-A1, U.S. Pat. No. 7,081,195, and U.S.patent application Ser. No. 11/543,707 filed on Oct. 4, 2008, U.S.patent application Ser. No. 11/543,539 filed on Oct. 4, 2008, U.S.patent application Ser. No. 11/543,683 filed on Oct. 4, 2008, and U.S.patent application Ser. No. 11/543,734 filed on Oct. 4, 2008, eachentitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR,” hereinincorporated by reference in their entirety. For example, in oneembodiment have an auxiliary working electrode, wherein the auxiliaryworking electrode comprises a wire formed from a conductive material,such as described with reference to the glucose-measuring workingelectrode above. Preferably, the reference electrode, which can functionas a reference electrode alone, or as a dual reference and counterelectrode, is formed from silver, Silver/Silver chloride, and the like.

In some embodiments, the electrodes are juxtapositioned and/or twistedwith or around each other; however other configurations are alsopossible. In one example, the auxiliary working electrode and referenceelectrode can be helically wound around the glucose-measuring workingelectrode. Alternatively, the auxiliary working electrode and referenceelectrode can be formed as a double helix around a length of theglucose-measuring working electrode. The assembly of wires can then beoptionally coated together with an insulating material, similar to thatdescribed above, in order to provide an insulating attachment. Someportion of the coated assembly structure is then stripped, for exampleusing an excimer laser, chemical etching, and the like, to expose thenecessary electroactive surfaces. In some alternative embodiments,additional electrodes can be included within the assembly, for example,a three-electrode system (including separate reference and counterelectrodes) as is appreciated by one skilled in the art.

In some alternative embodiments, the sensor is configured as adual-electrode system. In one such dual-electrode system, a firstelectrode functions as a hydrogen peroxide sensor including a membranesystem containing glucose-oxidase disposed thereon, which operates asdescribed herein. A second electrode is a hydrogen peroxide sensor thatis configured similar to the first electrode, but with a modifiedmembrane system (without active enzyme, for example). This secondelectrode provides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the insertedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S.Publication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some embodiments, the reference electrode can be disposed remotelyfrom the working electrode. In one embodiment, the reference electroderemains within the fluid flow, but is disposed within the fluid coupler.For example, the reference electrode can be coiled within the fluidcoupler such that it is contact with saline flowing into the host, butit is not in physical contact with the host's blood (except when bloodis withdrawn from the catheter). In another embodiment, the referenceelectrode is removed from fluid flow, but still maintains bodily fluidcontact. For example, the reference electrode can be wired to anadhesive patch that is adhered to the host, such that the referenceelectrode is in contact with the host's skin. In yet another embodiment,the reference electrode can be external from the system, such as but notlimited to in contact with the exterior of the ex vivo portion of thesystem, in fluid or electrical contact with a connected saline drip orother medical device, or in bodily contact, such as is generally donewith EKG electrical contacts. While not wishing to be bound by theory,it is believed to locating the reference electrode remotely from theworking electrode permits manufacture of a smaller sensor footprint(e.g., diameter) that will have relatively less affect on the host'sblood flow, such as less thrombosis, than a sensor having a relativelylarger footprint (e.g., wherein both the working electrode and thereference electrode are adjacent to each other and within the bloodpath).

In some embodiments of the sensor system, in vivo portion of the sensor(e.g., the tip 14 a) has an enlarged area (e.g., a bulbous, nailhead-shaped, football-shaped, cone-shaped, cylindrical, etc. portion) ascompared a substantial portion of the sensor (e.g., diameter of the invivo portion of the sensor). The sensor tip can be made bulbous by anyconvenient systems and methods known in the art, such as but not limitedto arc welding, crimping, smashing, welding, molding, heating, andplasma arc welding. While not wishing to be bound by theory, it isbelieved that an enlarged sensor tip (e.g., bulbous) will prevent vesselpiercing as the sensor is pushed forward into the vessel.

The sensor of the preferred embodiments is designed with a minimallyinvasive architecture so as to minimize reactions or effects on theblood flow (or on the sensor in the blood flow). Accordingly, the sensordesigns described herein, consider minimization of dimensions andarrangement of the electrodes and other components of the sensor system,particularly the in vivo portion of the sensor (or any portion of thesensor in fluid contact with the blood flow).

Accordingly, in some embodiments, a substantial portion of the in vivoportion of the sensor is designed with at least one dimension less thanabout 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004 inches. In someembodiments, a substantial portion of the sensor that is in fluidcontact with the blood flow is designed with at least one dimension lessthan about 0.015, 0.012, 0.010, 0.008, 0.006, 0.005, 0.004, 0.003,0.002, 0.001 inches. As one exemplary embodiment, a sensor such asdescribed in more detail with reference to FIGS. 1A to 1C is formed froma 0.004-inch conductive wire (e.g., platinum) for a diameter of about0.004 inches along a substantial portion of the sensor (e.g., in vivoportion or fluid contact portion). As another exemplary embodiment, asensor such as described in more detail with reference to FIGS. 1A to 1Cis formed from a 0.004 inch conductive wire and vapor deposited with aninsulator material for a diameter of about 0.005 inches along asubstantial portion of the sensor (e.g., in vivo portion or fluidcontact portion), after which a desired electroactive surface area canbe exposed. In the above two exemplary embodiments, the referenceelectrode can be located remote from the working electrode (e.g., formedfrom the conductive wire). While the devices and methods describedherein are directed to use within the host's blood stream, one skilledin the art will recognize that the systems, configurations, methods andprinciples of operation described herein can be incorporated into otheranalyte sensing devices, such as but not limited to subcutaneous devicesor wholly implantable devices such as described in U.S. Publication2006-0016700, which is incorporated herein by reference in its entirety.

FIG. 3C is a cross section of the sensor shown in FIG. 3B, taken at lineC-C. Preferably, a membrane system (see FIG. 3C) is deposited over theelectroactive surfaces of the sensor and includes a plurality of domainsor layers, such as described in more detail below, with reference toFIGS. 3B and 3C. The membrane system can be deposited on the exposedelectroactive surfaces using known thin film techniques (for example,spraying, electro-depositing, dipping, and the like). In one exemplaryembodiment, each domain is deposited by dipping the sensor into asolution and drawing out the sensor at a speed that provides theappropriate domain thickness. In general, the membrane system can bedisposed over (deposited on) the electroactive surfaces using methodsappreciated by one skilled in the art.

In general, the membrane system includes a plurality of domains, forexample, an electrode domain 347, an interference domain 348, an enzymedomain 349 (for example, including glucose oxidase), and a resistancedomain 350, as shown in FIG. 3C, and can include a high oxygensolubility domain, and/or a bioprotective domain (not shown), such as isdescribed in more detail in U.S. Publication No. US-2005-0245799-A1, andsuch as is described in more detail below. The membrane system can bedeposited on the exposed electroactive surfaces using known thin filmtechniques (for example, vapor deposition, spraying, electro-depositing,dipping, and the like). In alternative embodiments, however, other vapordeposition processes (e.g., physical and/or chemical vapor depositionprocesses) can be useful for providing one or more of the insulatingand/or membrane layers, including ultrasonic vapor deposition,electrostatic deposition, evaporative deposition, deposition bysputtering, pulsed laser deposition, high velocity oxygen fueldeposition, thermal evaporator deposition, electron beam evaporatordeposition, deposition by reactive sputtering molecular beam epitaxy,atmospheric pressure chemical vapor deposition (CVD), atomic layer CVD,hot wire CVD, low-pressure CVD, microwave plasma-assisted CVD,plasma-enhanced CVD, rapid thermal CVD, remote plasma-enhanced CVD, andultra-high vacuum CVD, for example. However, the membrane system can bedisposed over (or deposited on) the electroactive surfaces using anyknown method, as will be appreciated by one skilled in the art.

In some embodiments, one or more domains of the membrane systems areformed from materials such as described above in connection with theporous layer, such as silicone, polytetrafluoroethylene,polyethylene-co-tetrafluoroethylene, polyolefin, polyester,polycarbonate, biostable polytetrafluoroethylene, homopolymers,copolymers, terpolymers of polyurethanes, polypropylene (PP),polyvinylchloride (PVC), polyvinylidene fluoride (PVDF), polybutyleneterephthalate (PBT), polymethylmethacrylate (PMMA), polyether etherketone (PEEK), polyurethanes, cellulosic polymers, polysulfones andblock copolymers thereof including, for example, di-block, tri-block,alternating, random and graft copolymers. U.S. Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that may be applied to the preferredembodiments.

Electrode Domain

In selected embodiments, the membrane system comprises an electrodedomain. The electrode domain 347 is provided to ensure that anelectrochemical reaction occurs between the electroactive surfaces ofthe working electrode and the reference electrode, and thus theelectrode domain 347 is preferably situated more proximal to theelectroactive surfaces than the interference and/or enzyme domain.Preferably, the electrode domain includes a coating that maintains alayer of water at the electrochemically reactive surfaces of the sensor.In other words, the electrode domain is present to provide anenvironment between the surfaces of the working electrode and thereference electrode, which facilitates an electrochemical reactionbetween the electrodes. For example, a humectant in a binder materialcan be employed as an electrode domain; this allows for the fulltransport of ions in the aqueous environment. The electrode domain canalso assist in stabilizing the operation of the sensor by acceleratingelectrode start-up and drifting problems caused by inadequateelectrolyte. The material that forms the electrode domain can alsoprovide an environment that protects against pH-mediated damage that canresult from the formation of a large pH gradient due to theelectrochemical activity of the electrodes.

In one embodiment, the electrode domain 347 includes a flexible,water-swellable, hydrogel film having a “dry film” thickness of fromabout 0.05 micron or less to about 20 microns or more, more preferablyfrom about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more preferably stillfrom about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. “Dryfilm” thickness refers to the thickness of a cured film cast from acoating formulation by standard coating techniques.

In certain embodiments, the electrode domain 347 is formed of a curablemixture of a urethane polymer and a hydrophilic polymer. Particularlypreferred coatings are formed of a polyurethane polymer havingcarboxylate or hydroxyl functional groups and non-ionic hydrophilicpolyether segments, wherein the polyurethane polymer is crosslinked witha water-soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of about 50° C.

In some preferred embodiments, the electrode domain 347 is formed from ahydrophilic polymer such as polyvinylpyrrolidone (PVP). An electrodedomain formed from PVP has been shown to reduce break-in time of analytesensors; for example, a glucose sensor utilizing a cellulosic-basedinterference domain such as described in more detail below.

Preferably, the electrode domain is deposited by vapor deposition, spraycoating, dip coating, or other thin film techniques on the electroactivesurfaces of the sensor. In one preferred embodiment, the electrodedomain is formed by dip-coating the electroactive surfaces in anelectrode layer solution and curing the domain for a time of from about15 minutes to about 30 minutes at a temperature of from about 40° C. toabout 55° C. (and can be accomplished under vacuum (e.g., 20 to 30mmHg)). In embodiments wherein dip-coating is used to deposit theelectrode domain, a preferred insertion rate of from about 1 to about 3inches per minute into the electrode layer solution, with a preferreddwell time of from about 0.5 to about 2 minutes in the electrode layersolution, and a preferred withdrawal rate of from about 0.25 to about 2inches per minute from the electrode layer solution provide a functionalcoating. However, values outside of those set forth above can beacceptable or even desirable in certain embodiments, for example,depending upon solution viscosity and solution surface tension, as isappreciated by one skilled in the art. In one embodiment, theelectroactive surfaces of the electrode system are dip-coated one time(one layer) and cured at 50° C. under vacuum for 20 minutes.

Although an independent electrode domain 347 is described herein, insome embodiments sufficient hydrophilicity can be provided in theinterference domain and/or enzyme domain (the domain adjacent to theelectroactive surfaces) so as to provide for the full transport of ionsin the aqueous environment (e.g. without a distinct electrode domain).In these embodiments, an electrode domain is not necessary.

Interference Domain

Interferents are molecules or other species that are reduced or oxidizedat the electrochemically reactive surfaces of the sensor, eitherdirectly or via an electron transfer agent, to produce a false positiveanalyte signal. In preferred embodiments, an interference domain 348 isprovided that substantially restricts, resists, or blocks the flow ofone or more interfering species. Some known interfering species for aglucose sensor, as described in more detail above, includeacetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid. Ingeneral, the interference domain of the preferred embodiments is lesspermeable to one or more of the interfering species than to the analyte,e.g., glucose.

In one embodiment, the interference domain 348 is formed from one ormore cellulosic derivatives. In general, cellulosic derivatives includepolymers such as cellulose acetate, cellulose acetate butyrate,2-hydroxyethyl cellulose, cellulose acetate phthalate, cellulose acetatepropionate, cellulose acetate trimellitate, and the like.

In one preferred embodiment, the interference domain 348 is formed fromcellulose acetate butyrate. Cellulose acetate butyrate with a molecularweight of about 10,000 daltons to about 75,000 daltons, preferably fromabout 15,000, 20,000, or 25,000 daltons to about 50,000, 55,000, 60,000,65,000, or 70,000 daltons, and more preferably about 20,000 daltons isemployed. In certain embodiments, however, higher or lower molecularweights can be preferred. Additionally, a casting solution or dispersionof cellulose acetate butyrate at a weight percent of about 15% to about25%, preferably from about 15%, 16%, 17%, 18%, 19% to about 20%, 21%,22%, 23%, 24% or 25%, and more preferably about 18% is preferred.Preferably, the casting solution includes a solvent or solvent system,for example an acetone:ethanol solvent system. Higher or lowerconcentrations can be preferred in certain embodiments. A plurality oflayers of cellulose acetate butyrate can be advantageously combined toform the interference domain in some embodiments, for example, threelayers can be employed. It can be desirable to employ a mixture ofcellulose acetate butyrate components with different molecular weightsin a single solution, or to deposit multiple layers of cellulose acetatebutyrate from different solutions comprising cellulose acetate butyrateof different molecular weights, different concentrations, and/ordifferent chemistries (e.g., functional groups). It can also bedesirable to include additional substances in the casting solutions ordispersions, e.g., functionalizing agents, crosslinking agents, otherpolymeric substances, substances capable of modifying thehydrophilicity/hydrophobicity of the resulting layer, and the like.

In one alternative embodiment, the interference domain 348 is formedfrom cellulose acetate. Cellulose acetate with a molecular weight ofabout 30,000 daltons or less to about 100,000 daltons or more,preferably from about 35,000, 40,000, or 45,000 daltons to about 55,000,60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or 95,000daltons, and more preferably about 50,000 daltons is preferred.Additionally, a casting solution or dispersion of cellulose acetate at aweight percent of about 3% to about 10%, preferably from about 3.5%,4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5% to about 7.5%, 8.0%, 8.5%, 9.0%,or 9.5%, and more preferably about 8% is preferred. In certainembodiments, however, higher or lower molecular weights and/or celluloseacetate weight percentages can be preferred. It can be desirable toemploy a mixture of cellulose acetates with molecular weights in asingle solution, or to deposit multiple layers of cellulose acetate fromdifferent solutions comprising cellulose acetates of different molecularweights, different concentrations, or different chemistries (e.g.,functional groups). It can also be desirable to include additionalsubstances in the casting solutions or dispersions such as described inmore detail above.

Layer(s) prepared from combinations of cellulose acetate and celluloseacetate butyrate, or combinations of layer(s) of cellulose acetate andlayer(s) of cellulose acetate butyrate can also be employed to form theinterference domain 348.

In some alternative embodiments, additional polymers, such as Nafion®,can be used in combination with cellulosic derivatives to provideequivalent and/or enhanced function of the interference domain 348. Asone example, a 5 wt % Nafion® casting solution or dispersion can be usedin combination with a 8 wt % cellulose acetate casting solution ordispersion, e.g., by dip coating at least one layer of cellulose acetateand subsequently dip coating at least one layer Nafion® onto aneedle-type sensor such as described with reference to the preferredembodiments. Any number of coatings or layers formed in any order may besuitable for forming the interference domain of the preferredembodiments.

In some alternative embodiments, more than one cellulosic derivative canbe used to form the interference domain 348 of the preferredembodiments. In general, the formation of the interference domain on asurface utilizes a solvent or solvent system in order to solvate thecellulosic derivative (or other polymer) prior to film formationthereon. In preferred embodiments, acetone and ethanol are used assolvents for cellulose acetate; however one skilled in the artappreciates the numerous solvents that are suitable for use withcellulosic derivatives (and other polymers). Additionally, one skilledin the art appreciates that the preferred relative amounts of solventcan be dependent upon the cellulosic derivative (or other polymer) used,its molecular weight, its method of deposition, its desired thickness,and the like. However, a percent solute of from about 1% to about 25% ispreferably used to form the interference domain solution so as to yieldan interference domain having the desired properties. The cellulosicderivative (or other polymer) used, its molecular weight, method ofdeposition, and desired thickness can be adjusted, depending upon one ormore other of the parameters, and can be varied accordingly as isappreciated by one skilled in the art.

In some alternative embodiments, other polymer types that can beutilized as a base material for the interference domain 348 includingpolyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size, for example. In one such alternative embodiment,the interference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of low molecular weight species.The interference domain 348 is permeable to relatively low molecularweight substances, such as hydrogen peroxide, but restricts the passageof higher molecular weight substances, including glucose and ascorbicacid. Other systems and methods for reducing or eliminating interferencespecies that can be applied to the membrane system of the preferredembodiments are described in U.S. Publication No. US-2005-0115832-A1,U.S. Publication No. US-2005-0176136-A1, U.S. Publication No.US-2005-0161346-A1, and U.S. Publication No. US-2005-0143635-A1, U.S.Publication No. US-2006-0020187-A1, and U.S. patent application Ser. No.11/543,707 filed on Oct. 4, 2008, U.S. patent application Ser. No.11/543,539 filed on Oct. 4, 2008, U.S. patent application Ser. No.11/543,683 filed on Oct. 4, 2008, and U.S. patent application Ser. No.11/543,734 filed on Oct. 4, 2008, each entitled “DUAL ELECTRODE SYSTEMFOR A CONTINUOUS ANALYTE SENSOR,” all of which are incorporated hereinby reference in their entirety. In some alternative embodiments, adistinct interference domain is not included.

In preferred embodiments, the interference domain 348 is depositeddirectly onto the electroactive surfaces of the sensor for a domainthickness of from about 0.05 micron or less to about 20 microns or more,more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and morepreferably still from about 1, 1.5 or 2 microns to about 2.5 or 3microns. Thicker membranes can also be desirable in certain embodiments,but thinner membranes are generally preferred because they can have alower impact on the rate of diffusion of hydrogen peroxide from theenzyme membrane to the electrodes.

In general, the membrane systems of the preferred embodiments can beformed and/or deposited on the exposed electroactive surfaces (e.g., oneor more of the working and reference electrodes) using known thin filmtechniques (for example, casting, spray coating, drawing down,electro-depositing, dip coating, and the like), however casting or otherknown application techniques can also be utilized. Preferably, theinterference domain is deposited by vapor deposition, spray coating, ordip coating. In one exemplary embodiment of a needle-type(transcutaneous) sensor such as described herein, the interferencedomain is formed by dip coating the sensor into an interference domainsolution using an insertion rate of from about 20 inches/min to about 60inches/min, preferably 40 inches/min, a dwell time of from about 0minute to about 5 seconds, preferably 0 seconds, and a withdrawal rateof from about 20 inches/minute to about 60 inches/minute, preferablyabout 40 inches/minute, and curing (drying) the domain from about 1minute to about 30 minutes, preferably from about 3 minutes to about 15minutes (and can be accomplished at room temperature or under vacuum(e.g., 20 to 30 mmHg)). In one exemplary embodiment including celluloseacetate butyrate interference domain, a 3-minute cure (i.e., dry) timeis preferred between each layer applied. In another exemplary embodimentemploying a cellulose acetate interference domain, a 15 minute cure(i.e., dry) time is preferred between each layer applied.

The dip process can be repeated at least one time and up to 10 times ormore. The preferred number of repeated dip processes depends upon thecellulosic derivative(s) used, their concentration, conditions duringdeposition (e.g., dipping) and the desired thickness (e.g., sufficientthickness to provide functional blocking of (or resistance to) certaininterferents), and the like. In some embodiments, 1 to 3 microns may bepreferred for the interference domain thickness; however, values outsideof these can be acceptable or even desirable in certain embodiments, forexample, depending upon viscosity and surface tension, as is appreciatedby one skilled in the art. In one exemplary embodiment, an interferencedomain is formed from three layers of cellulose acetate butyrate. Inanother exemplary embodiment, an interference domain is formed from 10layers of cellulose acetate. In alternative embodiments, theinterference domain can be formed using any known method and combinationof cellulose acetate and cellulose acetate butyrate, as will beappreciated by one skilled in the art.

In some embodiments, the electroactive surface can be cleaned prior toapplication of the interference domain 348. In some embodiments, theinterference domain 348 of the preferred embodiments can be useful as abioprotective or biocompatible domain, namely, a domain that interfaceswith host tissue when implanted in an animal (e.g., a human) due to itsstability and biocompatibility.

Enzyme Domain

In preferred embodiments, the membrane system further includes an enzymedomain 349 disposed more distally from the electroactive surfaces thanthe interference domain 348; however other configurations can bedesirable. In the preferred embodiments, the enzyme domain provides anenzyme to catalyze the reaction of the analyte and its co-reactant, asdescribed in more detail below. In the preferred embodiments of aglucose sensor, the enzyme domain includes glucose oxidase; howeverother oxidases, for example, galactose oxidase or uricase oxidase, canalso be used.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response is preferably limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior is compensated for in forming the enzymedomain. Preferably, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, for example, silicone, orfluorocarbon, in order to provide a supply of excess oxygen duringtransient ischemia. Preferably, the enzyme is immobilized within thedomain. See, e.g., U.S. Publication No. US-2005-0054909-A1.

In preferred embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. However in some embodiments,the enzyme domain can be deposited directly onto the electroactivesurfaces. Preferably, the enzyme domain is deposited by spray or dipcoating. In one embodiment of needle-type (transcutaneous) sensor suchas described herein, the enzyme domain is formed by dip coating theinterference domain coated sensor into an enzyme domain solution andcuring the domain for from about 15 to about 30 minutes at a temperatureof from about 40° C. to about 55° C. (and can be accomplished undervacuum (e.g., 20 to 30 mmHg)). In embodiments wherein dip coating isused to deposit the enzyme domain at room temperature, a preferredinsertion rate of from about 0.25 inch per minute to about 3 inches perminute, with a preferred dwell time of from about 0.5 minutes to about 2minutes, and a preferred withdrawal rate of from about 0.25 inch perminute to about 2 inches per minute provides a functional coating.However, values outside of those set forth above can be acceptable oreven desirable in certain embodiments, for example, depending uponviscosity and surface tension, as is appreciated by one skilled in theart. In one embodiment, the enzyme domain is formed by dip coating twotimes (namely, forming two layers) in an enzyme domain solution andcuring at 50° C. under vacuum for 20 minutes. However, in someembodiments, the enzyme domain can be formed by dip coating and/or spraycoating one or more layers at a predetermined concentration of thecoating solution, insertion rate, dwell time, withdrawal rate, and/ordesired thickness.

Resistance Domain

In preferred embodiments, the membrane system includes a resistancedomain 350 disposed more distal from the electroactive surfaces than theenzyme domain. Although the following description is directed to aresistance domain for a glucose sensor, the resistance domain can bemodified for other analytes and co-reactants as well.

There exists a molar excess of glucose relative to the amount of oxygenin blood; that is, for every free oxygen molecule in extracellularfluid, there are typically more than 100 glucose molecules present (seeUpdike et al., Diabetes Care 5:207-21 (1982)). However, an immobilizedenzyme-based glucose sensor employing oxygen as co-reactant ispreferably supplied with oxygen in non-rate-limiting excess in order forthe sensor to respond linearly to changes in glucose concentration,while not responding to changes in oxygen concentration. Specifically,when a glucose-monitoring reaction is oxygen limited, linearity is notachieved above minimal concentrations of glucose. Without asemipermeable membrane situated over the enzyme domain to control theflux of glucose and oxygen, a linear response to glucose levels can beobtained only for glucose concentrations of up to about 40 mg/dL.However, in a clinical setting, a linear response to glucose levels isdesirable up to at least about 400 mg/dL.

The resistance domain includes a semipermeable membrane that controlsthe flux of oxygen and glucose to the underlying enzyme domain,preferably rendering oxygen in a non-rate-limiting excess. As a result,the upper limit of linearity of glucose measurement is extended to amuch higher value than that which is achieved without the resistancedomain. In one embodiment, the resistance domain exhibits an oxygen toglucose permeability ratio of from about 50:1 or less to about 400:1 ormore, preferably about 200:1. As a result, one-dimensional reactantdiffusion is adequate to provide excess oxygen at all reasonable glucoseand oxygen concentrations found in the subcutaneous matrix (See Rhodeset al., Anal. Chem., 66:1520-1529 (1994)).

In alternative embodiments, a lower ratio of oxygen-to-glucose can besufficient to provide excess oxygen by using a high oxygen solubilitydomain (for example, a silicone or fluorocarbon-based material ordomain) to enhance the supply/transport of oxygen to the enzyme domain.If more oxygen is supplied to the enzyme, then more glucose can also besupplied to the enzyme without creating an oxygen rate-limiting excess.In alternative embodiments, the resistance domain is formed from asilicone composition, such as is described in U.S. Publication No.US-2005-0090607-A1.

In a preferred embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated easily and reproducibly from commercially availablematerials. A suitable hydrophobic polymer component is a polyurethane,or polyetherurethaneurea. Polyurethane is a polymer produced by thecondensation reaction of a diisocyanate and a difunctionalhydroxyl-containing material. A polyurethaneurea is a polymer producedby the condensation reaction of a diisocyanate and a difunctionalamine-containing material. Preferred diisocyanates include aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of the membranesof preferred embodiments. The material that forms the basis of thehydrophobic matrix of the resistance domain can be any of those known inthe art as appropriate for use as membranes in sensor devices and ashaving sufficient permeability to allow relevant compounds to passthrough it, for example, to allow an oxygen molecule to pass through themembrane from the sample under examination in order to reach the activeenzyme or electrochemical electrodes. Examples of materials which can beused to make non-polyurethane type membranes include vinyl polymers,polyethers, polyesters, polyamides, inorganic polymers such aspolysiloxanes and polycarbosiloxanes, natural polymers such ascellulosic and protein based materials, and mixtures or combinationsthereof.

In a preferred embodiment, the hydrophilic polymer component ispolyethylene oxide. For example, one useful hydrophobic-hydrophiliccopolymer component is a polyurethane polymer that includes about 20%hydrophilic polyethylene oxide. The polyethylene oxide portions of thecopolymer are thermodynamically driven to separate from the hydrophobicportions of the copolymer and the hydrophobic polymer component. The 20%polyethylene oxide-based soft segment portion of the copolymer used toform the final blend affects the water pick-up and subsequent glucosepermeability of the membrane.

In some embodiments, the resistance domain is formed from a siliconepolymer modified to allow analyte (e.g., glucose) transport.

In some embodiments, the resistance domain is formed from a siliconepolymer/hydrophobic-hydrophilic polymer blend. In one embodiment, Thehydrophobic-hydrophilic polymer for use in the blend may be any suitablehydrophobic-hydrophilic polymer, including but not limited to componentssuch as polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers such as polyethyleneglycol or polypropylene oxide, and copolymers thereof, including, forexample, di-block, tri-block, alternating, random, comb, star,dendritic, and graft copolymers (block copolymers are discussed in U.S.Pat. Nos. 4,803,243 and 4,686,044, which are incorporated herein byreference). In one embodiment, the hydrophobic-hydrophilic polymer is acopolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).Suitable such polymers include, but are not limited to, PEO-PPO diblockcopolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblockcopolymers, alternating block copolymers of PEO-PPO, random copolymersof ethylene oxide and propylene oxide, and blends thereof. In someembodiments, the copolymers may be optionally substituted with hydroxysubstituents. Commercially available examples of PEO and PPO copolymersinclude the PLURONIC® brand of polymers available from BASF®. In oneembodiment, PLURONIC® F-127 is used. Other PLURONIC® polymers includePPO-PEO-PPO triblock copolymers (e.g., PLURONIC® R products). Othersuitable commercial polymers include, but are not limited to,SYNPERONICS® products available from UNIQEMA®. Co-pending U.S. patentapplication Ser. No. 11/404,417 and entitled, “SILICONE BASED MEMBRANESFOR USE IN IMPLANTABLE GLUCOSE SENSORS,” which is incorporated herein byreference in its entirety, describes systems and methods suitable forthe resistance and/or other domains of the membrane system of thepreferred embodiments.

In preferred embodiments, the resistance domain is deposited onto theenzyme domain to yield a domain thickness of from about 0.05 microns orless to about 20 microns or more, more preferably from about 0.05, 0.1,0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 19.5 microns, and more preferably still from about 2, 2.5 or 3microns to about 3.5, 4, 4.5, or 5 microns. Preferably, the resistancedomain is deposited onto the enzyme domain by vapor deposition, spraycoating, or dip coating. In one preferred embodiment, spray coating isthe preferred deposition technique. The spraying process atomizes andmists the solution, and therefore most or all of the solvent isevaporated prior to the coating material settling on the underlyingdomain, thereby minimizing contact of the solvent with the enzyme.

In another preferred embodiment, physical vapor deposition (e.g.,ultrasonic vapor deposition) is used for coating one or more of themembrane domain(s) onto the electrodes, wherein the vapor depositionapparatus and process include an ultrasonic nozzle that produces a mistof micro-droplets in a vacuum chamber. In these embodiments, themicro-droplets move turbulently within the vacuum chamber, isotropicallyimpacting and adhering to the surface of the substrate. Advantageously,vapor deposition as described above can be implemented to provide highproduction throughput of membrane deposition processes (e.g., at leastabout 20 to about 200 or more electrodes per chamber), greaterconsistency of the membrane on each sensor, and increased uniformity ofsensor performance, for example, as described below.

In some embodiments, depositing the resistance domain (for example, asdescribed in the preferred embodiments above) includes formation of amembrane system that substantially blocks or resists ascorbate (a knownelectrochemical interferant in hydrogen peroxide-measuring glucosesensors). While not wishing to be bound by theory, it is believed thatduring the process of depositing the resistance domain as described inthe preferred embodiments, a structural morphology is formed that ischaracterized in that ascorbate does not substantially permeatetherethrough.

In a preferred embodiment, the resistance domain is deposited on theenzyme domain by spray coating a solution of from about 1 wt. % to about5 wt. % polymer and from about 95 wt. % to about 99 wt. % solvent. Inspraying a solution of resistance domain material, including a solvent,onto the enzyme domain, it is desirable to mitigate or substantiallyreduce any contact with enzyme of any solvent in the spray solution thatcan deactivate the underlying enzyme of the enzyme domain.Tetrahydrofuran (THF) is one solvent that minimally or negligiblyaffects the enzyme of the enzyme domain upon spraying. Other solventscan also be suitable for use, as is appreciated by one skilled in theart.

Although a variety of spraying or deposition techniques can be used,spraying the resistance domain material and rotating the sensor at leastone time by 180° can typically provide adequate coverage by theresistance domain. Spraying the resistance domain material and rotatingthe sensor at least two times by 120° provides even greater coverage(one layer of 360° coverage), thereby ensuring resistivity to glucose,such as is described in more detail above.

In preferred embodiments, the resistance domain is spray coated andsubsequently cured for a time of from about 15 minutes to about 90minutes at a temperature of from about 40° C. to about 60° C. (and canbe accomplished under vacuum (e.g., from 20 to 30 mmHg)). A cure time ofup to about 90 minutes or more can be advantageous to ensure completedrying of the resistance domain.

In one embodiment, the resistance domain is formed by spray coating atleast six layers (namely, rotating the sensor seventeen times by 120°for at least six layers of 360° coverage) and curing at 50° C. undervacuum for 60 minutes. However, the resistance domain can be formed bydip coating or spray coating any layer or plurality of layers, dependingupon the concentration of the solution, insertion rate, dwell time,withdrawal rate, and/or the desired thickness of the resulting film.Additionally, curing in a convention oven can also be employed.

In certain embodiments, a variable frequency microwave oven can be usedto cure the membrane domains/layers. In general, microwave ovensdirectly excite the rotational mode of solvents. Consequently, microwaveovens cure coatings from the inside out rather than from the outside inas with conventional convection ovens. This direct rotational modeexcitation is responsible for the typically observed “fast” curingwithin a microwave oven. In contrast to conventional microwave ovens,which rely upon a fixed frequency of emission that can cause arcing ofdielectric (metallic) substrates if placed within a conventionalmicrowave oven, Variable Frequency Microwave (VFM) ovens emit thousandsof frequencies within 100 milliseconds, which substantially eliminatesarcing of dielectric substrates. Consequently, the membranedomains/layers can be cured even after deposition on metallic electrodesas described herein. While not wishing to be bound by theory, it isbelieve that VFM curing can increase the rate and completeness ofsolvent evaporation from a liquid membrane solution applied to a sensor,as compared to the rate and completeness of solvent evaporation observedfor curing in conventional convection ovens.

In certain embodiments, VFM is can be used together with convection ovencuring to further accelerate cure time. In some sensor applicationswherein the membrane is cured prior to application on the electrode(see, for example, U.S. Publication No. US-2005-0245799-A1, which isincorporated herein by reference in its entirety), conventionalmicrowave ovens (e.g., fixed frequency microwave ovens) can be used tocure the membrane layer.

Treatment of Interference Domain/Membrane System

Although the above-described methods generally include a curing step information of the membrane system, including the interference domain, thepreferred embodiments further include an additional treatment step,which can be performed directly after the formation of the interferencedomain and/or some time after the formation of the entire membranesystem (or anytime in between). In some embodiments, the additionaltreatment step is performed during (or in combination with)sterilization of the sensor.

In some embodiments, the membrane system (or interference domain) istreated by exposure to ionizing radiation, for example, electron beamradiation, UV radiation, X-ray radiation, gamma radiation, and the like.Alternatively, the membrane can be exposed to visible light whensuitable photoinitiators are incorporated into the interference domain.While not wishing to be bound by theory, it is believed that exposingthe interference domain to ionizing radiation substantially crosslinksthe interference domain and thereby creates a tighter, less permeablenetwork than an interference domain that has not been exposed toionizing radiation.

In some embodiments, the membrane system (or interference domain) iscrosslinked by forming free radicals, which may include the use ofionizing radiation, thermal initiators, chemical initiators,photoinitiators (e.g., UV and visible light), and the like. Any suitableinitiator or any suitable initiator system can be employed, for example,α-hydroxyketone, α-aminoketone, ammonium persulfate (APS), redox systemssuch as APS/bisulfite, or potassium permanganate. Suitable thermalinitiators include but are not limited to potassium persulfate, ammoniumpersulfate, sodium persulfate, and mixtures thereof.

In embodiments wherein electron beam radiation is used to treat themembrane system (or interference domain), a preferred exposure time isfrom about 6 k or 12 kGy to about 25 or 50 kGy, more preferably about 25kGy. However, one skilled in the art appreciates that choice ofmolecular weight, composition of cellulosic derivative (or otherpolymer), and/or the thickness of the layer can affect the preferredexposure time of membrane to radiation. Preferably, the exposure issufficient for substantially crosslinking the interference domain toform free radicals, but does not destroy or significantly break down themembrane or does not significantly damage the underlying electroactivesurfaces.

In embodiments wherein UV radiation is employed to treat the membrane,UV rays from about 200 nm to about 400 nm are preferred; however valuesoutside of this range can be employed in certain embodiments, dependentupon the cellulosic derivative and/or other polymer used.

In some embodiments, for example, wherein photoinitiators are employedto crosslink the interference domain, one or more additional domains canbe provided adjacent to the interference domain for preventingdelamination that may be caused by the crosslinking treatment. Theseadditional domains can be “tie layers” (i.e., film layers that enhanceadhesion of the interference domain to other domains of the membranesystem). In one exemplary embodiment, a membrane system is formed thatincludes the following domains: resistance domain, enzyme domain,electrode domain, and cellulosic-based interference domain, wherein theelectrode domain is configured to ensure adhesion between the enzymedomain and the interference domain. In embodiments whereinphotoinitiators are employed to crosslink the interference domain, UVradiation of greater than about 290 nm is preferred. Additionally, fromabout 0.01 to about 1 wt % photoinitiator is preferred weight-to-weightwith a preselected cellulosic polymer (e.g., cellulose acetate); howevervalues outside of this range can be desirable dependent upon thecellulosic polymer selected.

In general, sterilization of the transcutaneous sensor can be completedafter final assembly, utilizing methods such as electron beam radiation,gamma radiation, glutaraldehyde treatment, and the like. The sensor canbe sterilized prior to or after packaging. In an alternative embodiment,one or more sensors can be sterilized using variable frequency microwavechamber(s), which can increase the speed and reduce the cost of thesterilization process. In another alternative embodiment, one or moresensors can be sterilized using ethylene oxide (EtO) gas sterilization,for example, by treating with 100% ethylene oxide, which can be usedwhen the sensor electronics are not detachably connected to the sensorand/or when the sensor electronics must undergo a sterilization process.In one embodiment, one or more packaged sets of transcutaneous sensors(e.g., 1, 2, 3, 4, or 5 sensors or more) are sterilized simultaneously.

Therapeutic Agents

A variety of therapeutic (bioactive) agents can be used with the analytesensor system of the preferred embodiments, such as the analyte sensorsystem of the embodiments shown in FIGS. 1A-3C. In some embodiments, thetherapeutic agent is an anticoagulant. The term “anticoagulant” as usedherein is a broad term, and is to be given its ordinary and customarymeaning to a person of ordinary skill in the art (and is not to belimited to a special or customized meaning), and refers withoutlimitation to a substance the prevents coagulation (e.g., minimizes,reduces, or stops clotting of blood). In some embodiments, ananticoagulant is included in the analyte sensor system to preventcoagulation within or on the sensor (e.g., within or on the catheter orwithin or on the sensor). Suitable anticoagulants for incorporation intothe sensor system include, but are not limited to, vitamin K antagonists(e.g., Acenocoumarol, Clorindione, Dicumarol (Dicoumarol), Diphenadione,Ethyl biscoumacetate, Phenprocoumon, Phenindione, Tioclomarol, orWarfarin), heparin group anticoagulants (e.g., Platelet aggregationinhibitors: Antithrombin III, Bemiparin, Dalteparin, Danaparoid,Enoxaparin, Heparin, Nadroparin, Parnaparin, Reviparin, Sulodexide,Tinzaparin), other platelet aggregation inhibitors (e.g., Abciximab,Acetylsalicylic acid (Aspirin), Aloxiprin, Beraprost, Ditazole,Carbasalate calcium, Cloricromen, Clopidogrel, Dipyridamole,Epoprostenol, Eptifibatide, Indobufen, Iloprost, Picotamide,Ticlopidine, Tirofiban, Treprostinil, Triflusal), enzymes (e.g.,Alteplase, Ancrod, Anistreplase, Brinase, Drotrecogin alfa,Fibrinolysin, Protein C, Reteplase, Saruplase, Streptokinase,Tenecteplase, Urokinase), direct thrombin inhibitors (e.g., Argatroban,Bivalirudin, Desirudin, Lepirudin, Melagatran, Ximelagatran, otherantithrombotics (e.g., Dabigatran, Defibrotide, Dermatan sulfate,Fondaparinux, Rivaroxaban) and the like.

In one embodiment, heparin is incorporated into the analyte sensorsystem. In a further embodiment, heparin is coated on the catheterand/or sensor by dipping or spraying. While not wishing to be bound bytheory, it is believed that heparin coated on the catheter and/or sensorprevents aggregation and clotting of blood on the analyte sensor system,thereby preventing thromboembolization (e.g., prevention of blood flowby the thrombus or clot) and/or subsequent complications.

In some embodiments, the membrane system of the preferred embodimentspreferably include a bioactive agent, which is incorporated into atleast a portion of the membrane system, or which is incorporated intothe device and adapted to diffuse through the membrane.

There are a variety of systems and methods by which the bioactive agentis incorporated into the membrane of the preferred embodiments. In someembodiments, the bioactive agent is incorporated at the time ofmanufacture of the membrane system. For example, the bioactive agent canbe blended prior to curing the membrane system, or subsequent tomembrane system manufacture, for example, by coating, imbibing,solvent-casting, or sorption of the bioactive agent into the membranesystem. Although the bioactive agent is preferably incorporated into themembrane system, in some embodiments the bioactive agent can beadministered concurrently with, prior to, or after insertion of thedevice intravascularly, for example, by oral administration, or locally,for example, by subcutaneous injection near the implantation site. Acombination of bioactive agent incorporated in the membrane system andbioactive agent administration locally and/or systemically can bepreferred in certain embodiments.

In general, a bioactive agent can be incorporated into the membranesystem, and/or incorporated into the device and adapted to diffusetherefrom, in order to modify the tissue response of the host to themembrane. In some embodiments, the bioactive agent is incorporated onlyinto a portion of the membrane system adjacent to the sensing region ofthe device, over the entire surface of the device except over thesensing region, or any combination thereof, which can be helpful incontrolling different mechanisms and/or stages of thrombus formation. Insome alternative embodiments however, the bioactive agent isincorporated into the device proximal to the membrane system, such thatthe bioactive agent diffuses through the membrane system to the hostcirculatory system.

The bioactive agent can include a carrier matrix, wherein the matrixincludes one or more of collagen, a particulate matrix, a resorbable ornon-resorbable matrix, a controlled-release matrix, and/or a gel. Insome embodiments, the carrier matrix includes a reservoir, wherein abioactive agent is encapsulated within a microcapsule. The carriermatrix can include a system in which a bioactive agent is physicallyentrapped within a polymer network. In some embodiments, the bioactiveagent is cross-linked with the membrane system, while in others thebioactive agent is sorbed into the membrane system, for example, byadsorption, absorption, or imbibing. The bioactive agent can bedeposited in or on the membrane system, for example, by coating,filling, or solvent casting. In certain embodiments, ionic and nonionicsurfactants, detergents, micelles, emulsifiers, demulsifiers,stabilizers, aqueous and oleaginous carriers, solvents, preservatives,antioxidants, or buffering agents are used to incorporate the bioactiveagent into the membrane system. The bioactive agent can be incorporatedinto a polymer using techniques such as described above, and the polymercan be used to form the membrane system, coatings on the membranesystem, portions of the membrane system, and/or any portion of thesensor system.

The membrane system can be manufactured using techniques known in theart. The bioactive agent can be sorbed into the membrane system, forexample, by soaking the membrane system for a length of time (forexample, from about an hour or less to about a week or more, preferablyfrom about 4, 8, 12, 16, or 20 hours to about 1, 2, 3, 4, 5, or 7 days).

The bioactive agent can be blended into uncured polymer prior to formingthe membrane system. The membrane system is then cured and the bioactiveagent thereby cross-linked and/or encapsulated within the polymer thatforms the membrane system.

In yet another embodiment, microspheres are used to encapsulate thebioactive agent. The microspheres can be formed of biodegradablepolymers, most preferably synthetic polymers or natural polymers such asproteins and polysaccharides. As used herein, the term polymer is usedto refer to both to synthetic polymers and proteins. U.S. Pat. No.6,281,015, which is incorporated herein by reference in its entirety,discloses some systems and methods that can be used in conjunction withthe preferred embodiments. In general, bioactive agents can beincorporated in (1) the polymer matrix forming the microspheres, (2)microparticle(s) surrounded by the polymer which forms the microspheres,(3) a polymer core within a protein microsphere, (4) a polymer coatingaround a polymer microsphere, (5) mixed in with microspheres aggregatedinto a larger form, or (6) a combination thereof. Bioactive agents canbe incorporated as particulates or by co-dissolving the factors with thepolymer. Stabilizers can be incorporated by addition of the stabilizersto the factor solution prior to formation of the microspheres.

The bioactive agent can be incorporated into a hydrogel and coated orotherwise deposited in or on the membrane system. Some hydrogelssuitable for use in the preferred embodiments include cross-linked,hydrophilic, three-dimensional polymer networks that are highlypermeable to the bioactive agent and are triggered to release thebioactive agent based on a stimulus.

The bioactive agent can be incorporated into the membrane system bysolvent casting, wherein a solution including dissolved bioactive agentis disposed on the surface of the membrane system, after which thesolvent is removed to form a coating on the membrane surface.

The bioactive agent can be compounded into a plug of material, which isplaced within the device, such as is described in U.S. Pat. Nos.4,506,680 and 5,282,844, which are incorporated herein by reference intheir entirety. In some embodiments, it is preferred to dispose the plugbeneath a membrane system; in this way, the bioactive agent iscontrolled by diffusion through the membrane, which provides a mechanismfor sustained-release of the bioactive agent in the host.

Release of Bioactive Agents

Numerous variables can affect the pharmacokinetics of bioactive agentrelease. The bioactive agents of the preferred embodiments can beoptimized for short- and/or long-term release. In some embodiments, thebioactive agents of the preferred embodiments are designed to aid orovercome factors associated with short-term effects (e.g., acuteinflammation and/or thrombosis) of sensor insertion. In someembodiments, the bioactive agents of the preferred embodiments aredesigned to aid or overcome factors associated with long-term effects,for example, chronic inflammation or build-up of fibrotic tissue and/orplaque material. In some embodiments, the bioactive agents of thepreferred embodiments combine short- and long-term release to exploitthe benefits of both.

As used herein, “controlled,” “sustained,” or “extended” release of thefactors can be continuous or discontinuous, linear or non-linear. Thiscan be accomplished using one or more types of polymer compositions,drug loadings, selections of excipients or degradation enhancers, orother modifications, administered alone, in combination or sequentiallyto produce the desired effect.

Short-term release of the bioactive agent in the preferred embodimentsgenerally refers to release over a period of from about a few minutes orhours to about 2, 3, 4, 5, 6, or 7 days or more.

Loading of Bioactive Agents

The amount of loading of the bioactive agent into the membrane systemcan depend upon several factors. For example, the bioactive agent dosageand duration can vary with the intended use of the membrane system, forexample, the intended length of use of the device and the like;differences among patients in the effective dose of bioactive agent;location and methods of loading the bioactive agent; and release ratesassociated with bioactive agents and optionally their carrier matrix.Therefore, one skilled in the art will appreciate the variability in thelevels of loading the bioactive agent, for the reasons described above.

In some embodiments, wherein the bioactive agent is incorporated intothe membrane system without a carrier matrix, the preferred level ofloading of the bioactive agent into the membrane system can varydepending upon the nature of the bioactive agent. The level of loadingof the bioactive agent is preferably sufficiently high such that abiological effect (e.g., thrombosis prevention) is observed. Above thisthreshold, bioactive agent can be loaded into the membrane system so asto imbibe up to 100% of the solid portions, cover all accessiblesurfaces of the membrane, and/or fill up to 100% of the accessiblecavity space. Typically, the level of loading (based on the weight ofbioactive agent(s), membrane system, and other substances present) isfrom about 1 ppm or less to about 1000 ppm or more, preferably fromabout 2, 3, 4, or 5 ppm up to about 10, 25, 50, 75, 100, 200, 300, 400,500, 600, 700, 800, or 900 ppm. In certain embodiments, the level ofloading can be 1 wt. % or less up to about 50 wt. % or more, preferablyfrom about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 wt. % up to about 25,30, 35, 40, or 45 wt. %.

When the bioactive agent is incorporated into the membrane system with acarrier matrix, such as a gel, the gel concentration can be optimized,for example, loaded with one or more test loadings of the bioactiveagent. It is generally preferred that the gel contain from about 0.1 orless to about 50 wt. % or more of the bioactive agent(s), preferablyfrom about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 wt. % to about 6,7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45 wt. % or more bioactiveagent(s), more preferably from about 1, 2, or 3 wt. % to about 4 or 5wt. % of the bioactive agent(s). Substances that are not bioactive canalso be incorporated into the matrix.

Referring now to microencapsulated bioactive agents, the release of theagents from these polymeric systems generally occur by two differentmechanisms. The bioactive agent can be released by diffusion throughaqueous filled channels generated in the dosage form by the dissolutionof the agent or by voids created by the removal of the polymer solventor a pore forming agent during the original micro-encapsulation.Alternatively, release can be enhanced due to the degradation of theencapsulating polymer. With time, the polymer erodes and generatesincreased porosity and microstructure within the device. This createsadditional pathways for release of the bioactive agent.

In some embodiments, the sensor is designed to be bioinert, e.g., by theuse of bioinert materials. Bioinert materials do not substantially causeany response from the host. As a result, cells can live adjacent to thematerial but do not form a bond with it. Bioinert materials include butare not limited to alumina, zirconia, titanium oxide or other bioinertmaterials generally used in the “catheter/catheterization” art. Whilenot wishing to be bound by theory, it is believed that inclusion of abioinert material in or on the sensor can reduce attachment of bloodcells or proteins to the sensor, thrombosis or other host reactions tothe sensor.

Sensor Electronics

The analyte sensor system has electronics, also referred to as a“computer system” that can include hardware, firmware, and/or softwarethat enable measurement and processing of data associated with analytelevels in the host. In one exemplary embodiment, the electronics includea potentiostat, a power source for providing power to the sensor, andother components useful for signal processing. In another exemplaryembodiment, the electronics include an RF module for transmitting datafrom sensor electronics to a receiver remote from the sensor. In anotherexemplary embodiment, the sensor electronics are wired to a receiver,which records the data and optionally transmits the data to a remotelocation, such as but not limited to a nurse's station, for tracking thehost's progress and to alarm the staff is a hypoglycemic episode occurs.

Various components of the electronics of the sensor system can bedisposed on or proximal to the analyte sensor, such as but not limitedto disposed on the fluid coupler 20 of the system, such as theembodiment shown in FIG. 1A. In another embodiment, wherein the sensoris integrally formed on the catheter (e.g., see FIG. 2A) and theelectronics are disposed on or proximal to the connector 218. In someembodiments, only a portion of the electronics (e.g., the potentiostat)is disposed on the device (e.g., proximal to the sensor), while theremaining electronics are disposed remotely from the device, such as ona stand or by the bedside. In a further embodiment, a portion of theelectronics can be disposed in a central location, such as a nurse'sstation.

In additional embodiments, some or all of the electronics can be inwired or wireless communication with the sensor and/or other portions ofthe electronics. For example, a potentiostat disposed on the device canbe wired to the remaining electronics (e.g., a processor, a recorder, atransmitter, a receiver, etc.), which reside on the bedside. In anotherexample, some portion of the electronics is wirelessly connected toanother portion of the electronics, such as by infrared (IR) or RF. Inone embodiment, a potentiostat resides on the fluid coupler and isconnected to a receiver by RF; accordingly, a battery, RF transmitter,and/or other minimally necessary electronics are provided with the fluidcoupler and the receiver includes an RF receiver.

Preferably, the potentiostat is operably connected to the electrode(s)(such as described above), which biases the sensor to enable measurementof a current signal indicative of the analyte concentration in the host(also referred to as the analog portion). In some embodiments, thepotentiostat includes a resistor that translates the current intovoltage. In some alternative embodiments, a current to frequencyconverter is provided that is configured to continuously integrate themeasured current, for example, using a charge counting device.

In some embodiments, the electronics include an A/D converter thatdigitizes the analog signal into a digital signal, also referred to as“counts” for processing. Accordingly, the resulting raw data stream incounts, also referred to as raw sensor data, is directly related to thecurrent measured by the potentiostat.

Typically, the electronics include a processor module that includes thecentral control unit that controls the processing of the sensor system.In some embodiments, the processor module includes a microprocessor,however a computer system other than a microprocessor can be used toprocess data as described herein, for example an ASIC can be used forsome or all of the sensor's central processing. The processor typicallyprovides semi-permanent storage of data, for example, storing data suchas sensor identifier (ID) and programming to process data streams (forexample, programming for data smoothing and/or replacement of signalartifacts such as is described in U.S. Publication No.US-2005-0043598-A1). The processor additionally can be used for thesystem's cache memory, for example for temporarily storing recent sensordata. In some embodiments, the processor module comprises memory storagecomponents such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM,EEPROM, rewritable ROMs, flash memory, and the like.

In some embodiments, the processor module comprises a digital filter,for example, an infinite impulse response (IIR) or finite impulseresponse (FIR) filter, configured to smooth the raw data stream from theA/D converter. Generally, digital filters are programmed to filter datasampled at a predetermined time interval (also referred to as a samplerate). In some embodiments, wherein the potentiostat is configured tomeasure the analyte at discrete time intervals, these time intervalsdetermine the sample rate of the digital filter. In some alternativeembodiments, wherein the potentiostat is configured to continuouslymeasure the analyte, for example, using a current-to-frequency converteras described above, the processor module can be programmed to request adigital value from the A/D converter at a predetermined time interval,also referred to as the acquisition time. In these alternativeembodiments, the values obtained by the processor are advantageouslyaveraged over the acquisition time due the continuity of the currentmeasurement. Accordingly, the acquisition time determines the samplerate of the digital filter. In preferred embodiments, the processormodule is configured with a programmable acquisition time, namely, thepredetermined time interval for requesting the digital value from theA/D converter is programmable by a user within the digital circuitry ofthe processor module. An acquisition time of from about 2 seconds toabout 512 seconds is preferred; however any acquisition time can beprogrammed into the processor module. A programmable acquisition time isadvantageous in optimizing noise filtration, time lag, andprocessing/battery power.

In some embodiments, the processor module is configured to build thedata packet for transmission to an outside source, for example, an RFtransmission to a receiver. Generally, the data packet comprises aplurality of bits that can include a preamble, a unique identifieridentifying the electronics unit, the receiver, or both, (e.g., sensorID code), data (e.g., raw data, filtered data, and/or an integratedvalue) and/or error detection or correction. Preferably, the data(transmission) packet has a length of from about 8 bits to about 128bits, preferably about 48 bits; however, larger or smaller packets canbe desirable in certain embodiments. The processor module can beconfigured to transmit any combination of raw and/or filtered data. Inone exemplary embodiment, the transmission packet contains a fixedpreamble, a unique ID of the electronics unit, a single five-minuteaverage (e.g., integrated) sensor data value, and a cyclic redundancycode (CRC).

In some embodiments, the processor module further comprises atransmitter portion that determines the transmission interval of thesensor data to a receiver, and the like. In some embodiments, thetransmitter portion, which determines the interval of transmission, isconfigured to be programmable. In one such embodiment, a coefficient canbe chosen (e.g., a number of from about 1 to about 100, or more),wherein the coefficient is multiplied by the acquisition time (orsampling rate), such as described above, to define the transmissioninterval of the data packet. Thus, in some embodiments, the transmissioninterval is programmable from about 2 seconds to about 850 minutes, morepreferably from about 30 second to about 5 minutes; however, anytransmission interval can be programmable or programmed into theprocessor module. However, a variety of alternative systems and methodsfor providing a programmable transmission interval can also be employed.By providing a programmable transmission interval, data transmission canbe customized to meet a variety of design criteria (e.g., reducedbattery consumption, timeliness of reporting sensor values, etc.)

In some embodiments, the processor further performs the processing, suchas storing data, analyzing data streams, calibrating analyte sensordata, estimating analyte values, comparing estimated analyte values withtime corresponding measured analyte values, analyzing a variation ofestimated analyte values, downloading data, and controlling the userinterface by providing analyte values, prompts, messages, warnings,alarms, and the like. In such cases, the processor includes hardware andsoftware that performs the processing described herein, for exampleflash memory provides permanent or semi-permanent storage of data,storing data such as sensor ID, receiver ID, and programming to processdata streams (for example, programming for performing estimation andother algorithms described elsewhere herein) and random access memory(RAM) stores the system's cache memory and is helpful in dataprocessing. Alternatively, some portion of the data processing (such asdescribed with reference to the processor elsewhere herein) can beaccomplished at another (e.g., remote) processor and can be configuredto be in wired or wireless connection therewith.

In some embodiments, an output module, which is integral with and/oroperatively connected with the processor, includes programming forgenerating output based on the data stream received from the sensorsystem and it's processing incurred in the processor. In someembodiments, output is generated via a user interface.

In some embodiments, a user interface is provided integral with (e.g.,on the patient inserted medical device), proximal to (e.g., a receivernear the medical device including bedside or on a stand), or remote fromthe sensor electronics (e.g., at a central station such as a nurse'sstation), wherein the user interface comprises a keyboard, speaker,vibrator, backlight, liquid crystal display (LCD) screen, and one ormore buttons. The components that comprise the user interface includecontrols to allow interaction of the user with the sensor system. Thekeyboard can allow, for example, input of user information, such asmealtime, exercise, insulin administration, customized therapyrecommendations, and reference analyte values. The speaker can produce,for example, audible signals or alerts for conditions such as presentand/or estimated hyperglycemic or hypoglycemic conditions. The vibratorcan provide, for example, tactile signals or alerts for reasons such asdescribed with reference to the speaker, above. The backlight can beprovided, for example, to aid a user in reading the LCD in low lightconditions. The LCD can be provided, for example, to provide the userwith visual data output, such as is described in U.S. Publication No.US-2005-0203360-A1. In some embodiments, the LCD is a touch-activatedscreen, enabling each selection by a user, for example, from a menu onthe screen. The buttons can provide for toggle, menu selection, optionselection, mode selection, and reset, for example. In some alternativeembodiments, a microphone can be provided to allow for voice-activatedcontrol.

In some embodiments, prompts or messages can be displayed on the userinterface to convey information to the user, such as reference outliervalues, requests for reference analyte values, therapy recommendations,deviation of the measured analyte values from the estimated analytevalues, and the like. Additionally, prompts can be displayed to guidethe user through calibration or trouble-shooting of the calibration.

Additionally, data output from the output module can provide wired orwireless, one- or two-way communication between the user interface andan external device. The external device can be any device that whereininterfaces or communicates with the user interface. In some embodiments,the external device is a computer, and the system is able to downloadhistorical data for retrospective analysis by the patient or physician,for example. In some embodiments, the external device is a modem orother telecommunications station, and the system is able to send alerts,warnings, emergency messages, and the like, via telecommunication linesto another party, such as a doctor or family member. In someembodiments, the external device is an insulin pen, and the system isable to communicate therapy recommendations, such as insulin amount andtime to the insulin pen. In some embodiments, the external device is aninsulin pump, and the system is able to communicate therapyrecommendations, such as insulin amount and time to the insulin pump.The external device can include other technology or medical devices, forexample pacemakers, implanted analyte sensor patches, other infusiondevices, telemetry devices, and the like.

The user interface, including keyboard, buttons, a microphone (notshown), and optionally the external device, can be configured to allowinput of data. Data input can be helpful in obtaining information aboutthe patient (for example, meal time, insulin administration, and thelike), receiving instructions from a physician (for example, customizedtherapy recommendations, targets, and the like), and downloadingsoftware updates, for example. Keyboard, buttons, touch-screen, andmicrophone are all examples of mechanisms by which a user can input datadirectly into the receiver. A server, personal computer, personaldigital assistant, insulin pump, and insulin pen are examples ofexternal devices that can provide useful information to the receiver.Other devices internal or external to the sensor that measure otheraspects of a patient's body (for example, temperature sensor,accelerometer, heart rate monitor, oxygen monitor, and the like) can beused to provide input helpful in data processing. In one embodiment, theuser interface can prompt the patient to select an activity most closelyrelated to their present activity, such as medication taken, surgicalprocedures, and the like, which can be helpful in linking to anindividual's physiological patterns, or other data processing. Inanother embodiment, a temperature sensor and/or heart rate monitor canprovide information helpful in linking activity, metabolism, and glucoseexcursions of an individual. While a few examples of data input havebeen provided here, a variety of information can be input, which can behelpful in data processing.

Algorithms

In some embodiments, calibration of an analyte sensor can be required,which includes data processing that converts sensor data signal into anestimated analyte measurement that is meaningful to a user. In general,the sensor system has a computer system (e.g., within the electronics)that receives sensor data (e.g., a data stream), including one or moretime-spaced sensor data points, measured by the sensor. The sensor datapoint(s) can be smoothed (filtered) in certain embodiments using afilter, for example, a finite impulse response (FIR) or infinite impulseresponse (IIR) filter. During the initialization of the sensor, prior toinitial calibration, the system can receive and store uncalibratedsensor data, however it can be configured to not display any data to theuser until initial calibration and, optionally, stabilization of thesensor has been established. In some embodiments, the data stream can beevaluated to determine sensor break-in (equilibration of the sensor invitro or in vivo).

In some embodiments, the system is configured to receive reference datafrom a reference analyte monitor, including one or more reference datapoints, also referred to as calibration information in some embodiments.The monitor can be of any suitable configuration. For example, in oneembodiment, the reference analyte points can comprise results from aself-monitored blood analyte test (e.g., from a finger stick test), suchas those described in U.S. Pat. Nos. 6,045,567; 6,156,051; 6,197,040;6,284,125; 6,413,410; and 6,733,655. In one such embodiment, the usercan administer a self-monitored blood analyte test to obtain an analytevalue (e.g., point) using any suitable analyte sensor, and then enterthe numeric analyte value into the computer system. In another suchembodiment, a self-monitored blood analyte test comprises a wired orwireless connection to the computer system so that the user simplyinitiates a connection between the two devices, and the referenceanalyte data is passed or downloaded between the self-monitored bloodanalyte test and the system. In yet another such embodiment, theself-monitored analyte test is integral with the receiver so that theuser simply provides a blood sample to the receiver, and the receiverruns the analyte test to determine a reference analyte value.

In some alternative embodiments, the reference data is based on sensordata from another substantially continuous analyte sensor such asdescribed herein, or another type of suitable continuous analyte sensor.In an embodiment employing a series of two or more continuous sensors,the sensors can be employed so that they provide sensor data in discreteor overlapping periods. In such embodiments, the sensor data from onecontinuous sensor can be used to calibrate another continuous sensor, orbe used to confirm the validity of a subsequently employed continuoussensor.

In some embodiments, the sensor system is coupled to a blood analysisdevice that periodically or intermittently collects a sample of thehost's blood (e.g., through the sensor system) and measures the host'sglucose concentration. In some embodiments, the blood analysis devicecollects a blood sample from the host about every 30 minutes, everyhour, or every few hours (e.g., 2, 3, 4, 5, 6, 8, 9 or 10 hours orlonger). In other embodiments, the blood analysis device can beactivated manually (e.g., by a healthcare worker) to collect and analyzea blood sample from the host. The glucose concentration data generatedby the blood analysis device can be used by the sensor system forcalibration data. In some embodiments, the sensor system canelectronically receive (either wired or wirelessly) these calibrationdata (from the blood analysis device). In other embodiments, thesecalibration data can be entered into the sensor system (e.g., sensorsystem electronics) by hand (e.g., manually entered by a healthcareworker).

In some embodiments, the sensor system is provided with one or morecalibration solutions (e.g., glucose solutions). In some embodiments,the sensor is shipped in a calibration solution (e.g., soaked). Thesensor is activated to calibrate itself (using the calibration solutionin which it was shipped) before insertion into the host. In someembodiments, the sensor is shipped (e.g., soaked or dry) with one ormore vials of calibration solution. The sensor can be soaked (e.g.,sequentially) in the vial(s) of calibration solution; calibration datapoints collected and the sensor calibrated using those calibrationpoints, before inserting the sensor into the host.

In one exemplary embodiment, the sensor is a glucose sensor, and it isshipped soaking in a sterile 50-mg/dl glucose solution with twoaccompanying calibration solutions (e.g., 100-mg/dl and 200-mg/dlsterile glucose solutions). Prior to insertion into the host,calibration data points are collected with the sensor in the 50-mg/dl,100-mg/dl and 200-mg/dl glucose solutions respectively. The sensorsystem can be calibrated using the collected calibration data points(e.g., using regression as described in more detail elsewhere herein).In an alternative exemplary embodiment, the sensor is shipped dry (e.g.,not soaking in a solution or buffer) with at least one calibrationsolution, for calibrating the sensor prior to insertion into the host.In some embodiments, a hand held glucose monitor (e.g., SMBG devicedescribed herein) can test the calibration solutions to generatecalibration data points, which are transferred electronically ormanually to the sensor system for calibration.

In some embodiments, a data matching module, also referred to as theprocessor module, matches reference data (e.g., one or more referenceanalyte data points) with substantially time corresponding sensor data(e.g., one or more sensor data points) to provide one or more matcheddata pairs. One reference data point can be matched to one timecorresponding sensor data point to form a matched data pair.Alternatively, a plurality of reference data points can be averaged(e.g., equally or non-equally weighted average, mean-value, median, andthe like) and matched to one time corresponding sensor data point toform a matched data pair, one reference data point can be matched to aplurality of time corresponding sensor data points averaged to form amatched data pair, or a plurality of reference data points can beaveraged and matched to a plurality of time corresponding sensor datapoints averaged to form a matched data pair.

In some embodiments, a calibration set module, also referred to as thecalibration module or processor module, forms an initial calibration setfrom a set of one or more matched data pairs, which are used todetermine the relationship between the reference analyte data and thesensor analyte data. The matched data pairs, which make up the initialcalibration set, can be selected according to predetermined criteria.The criteria for the initial calibration set can be the same as, ordifferent from, the criteria for the updated calibration sets. Incertain embodiments, the number (n) of data pair(s) selected for theinitial calibration set is one. In other embodiments, n data pairs areselected for the initial calibration set wherein n is a function of thefrequency of the received reference data points. In various embodiments,two data pairs make up the initial calibration set or six data pairsmake up the initial calibration set. In an embodiment wherein asubstantially continuous analyte sensor provides reference data,numerous data points are used to provide reference data from more than 6data pairs (e.g., dozens or even hundreds of data pairs). In oneexemplary embodiment, a substantially continuous analyte sensor provides288 reference data points per day (every five minutes for twenty-fourhours), thereby providing an opportunity for a matched data pair 288times per day, for example. While specific numbers of matched data pairsare referred to in the preferred embodiments, any suitable number ofmatched data pairs per a given time period can be employed.

In some embodiments, a conversion function module, also referred to asthe conversion module or processor module, uses the calibration set tocreate a conversion function. The conversion function substantiallydefines the relationship between the reference analyte data and theanalyte sensor data.

A variety of known methods can be used with the preferred embodiments tocreate the conversion function from the calibration set. In oneembodiment, wherein a plurality of matched data points form thecalibration set, a linear least squares regression is used to calculatethe conversion function; for example, this regression calculates a slopeand an offset using the equation y=m×+b. A variety of regression orother conversion schemes can be implemented herein.

In some alternative embodiments, the sensor is a dual-electrode system.In one such dual-electrode system, a first electrode functions as ahydrogen peroxide sensor including a membrane system containingglucose-oxidase disposed thereon, which operates as described herein. Asecond electrode is a hydrogen peroxide sensor that is configuredsimilar to the first electrode, but with a modified membrane system(with the enzyme domain removed, for example). This second electrodeprovides a signal composed mostly of the baseline signal, b.

In some dual-electrode systems, the baseline signal is (electronicallyor digitally) subtracted from the glucose signal to obtain a glucosesignal substantially without baseline. Accordingly, calibration of theresultant difference signal can be performed by solving the equationy=mx with a single paired measurement. Calibration of the implantedsensor in this alternative embodiment can be made less dependent on thevalues/range of the paired measurements, less sensitive to error inmanual blood glucose measurements, and can facilitate the sensor's useas a primary source of glucose information for the user. U.S.Publication No. US-2005-0143635-A1 describes systems and methods forsubtracting the baseline from a sensor signal.

In some alternative dual-electrode system embodiments, the analytesensor is configured to transmit signals obtained from each electrodeseparately (e.g., without subtraction of the baseline signal). In thisway, the receiver can process these signals to determine additionalinformation about the sensor and/or analyte concentration. For example,by comparing the signals from the first and second electrodes, changesin baseline and/or sensitivity can be detected and/or measured and usedto update calibration (e.g., without the use of a reference analytevalue). In one such example, by monitoring the corresponding first andsecond signals over time, an amount of signal contributed by baselinecan be measured. In another such example, by comparing fluctuations inthe correlating signals over time, changes in sensitivity can bedetected and/or measured.

In some alternative embodiments, a regression equation y=m×+b is used tocalculate the conversion function; however, prior information can beprovided for m and/or b, thereby enabling calibration to occur withfewer paired measurements. In one calibration technique, priorinformation (e.g., obtained from in vivo or in vitro tests) determines asensitivity of the sensor and/or the baseline signal of the sensor byanalyzing sensor data from measurements taken by the sensor (e.g., priorto inserting the sensor). For example, if there exists a predictiverelationship between in vitro sensor parameters and in vivo parameters,then this information can be used by the calibration procedure. Forexample, if a predictive relationship exists between in vitrosensitivity and in vivo sensitivity, m≈f(m_(in vitro)), then thepredicted m can be used, along with a single matched pair, to solve forb (b=y−mx). If, in addition, b can be assumed=0, for example with adual-electrode configuration that enables subtraction of the baselinefrom the signal such as described above, then both m and b are known apriori, matched pairs are not needed for calibration, and the sensor canbe completely calibrated e.g. without the need for reference analytevalues (e.g. values obtained after implantation in vivo.)

In another alternative embodiment, prior information can be provided toguide or validate the baseline (b) and/or sensitivity (m) determinedfrom the regression analysis. In this embodiment, boundaries can be setfor the regression line that defines the conversion function such thatworking sensors are calibrated accurately and easily (with two points),and non-working sensors are prevented from being calibrated. If theboundaries are drawn too tightly, a working sensor may not enter intocalibration. Likewise, if the boundaries are drawn too loosely, thescheme can result in inaccurate calibration or can permit non-workingsensors to enter into calibration. For example, subsequent to performingregression, the resulting slope and/or baseline are tested to determinewhether they fall within a predetermined acceptable threshold(boundaries). These predetermined acceptable boundaries can be obtainedfrom in vivo or in vitro tests (e.g., by a retrospective analysis ofsensor sensitivities and/or baselines collected from a set ofsensors/patients, assuming that the set is representative of futuredata).

In some alternative embodiments, the sensor system does not requireinitial and/or update calibration by the host; in these alternativeembodiments, also referred to as “zero-point calibration” embodiments,use of the sensor system without requiring a reference analytemeasurement for initial and/or update calibration is enabled. Ingeneral, the systems and methods of the preferred embodiments providefor stable and repeatable sensor manufacture, particularly when tightlycontrolled manufacturing processes are utilized. Namely, a batch ofsensors of the preferred embodiments can be designed with substantiallythe same baseline (b) and/or sensitivity (m) (+/−10%) when tested invitro. Additionally, the sensor of the preferred embodiments can bedesigned for repeatable m and b in vivo. Thus, an initial calibrationfactor (conversion function) can be programmed into the sensor (sensorelectronics and/or receiver electronics) that enables conversion of rawsensor data into calibrated sensor data solely using informationobtained prior to implantation (namely, initial calibration does notrequire a reference analyte value). Additionally, to obviate the needfor recalibration (update calibration) during the life of the sensor,the sensor is designed to minimize drift of the sensitivity and/orbaseline over time in vivo. Accordingly, the preferred embodiments canbe manufactured for zero point calibration.

In some embodiments, a sensor data transformation module, also referredto as the calibration module, conversion module, or processor module,uses the conversion function to transform sensor data into substantiallyreal-time analyte value estimates, also referred to as calibrated data,or converted sensor data, as sensor data is continuously (orintermittently) received from the sensor. For example, the sensor data,which can be provided to the receiver in “counts,” is translated in toestimate analyte value(s) in mg/dL. In other words, the offset value atany given point in time can be subtracted from the raw value (e.g., incounts) and divided by the slope to obtain the estimate analyte value:

${{mg}/{dL}} = \frac{\left( {{rawvalue} - {offset}} \right)}{slope}$

In some embodiments, an output module provides output to the user viathe user interface. The output is representative of the estimatedanalyte value, which is determined by converting the sensor data into ameaningful analyte value. User output can be in the form of a numericestimated analyte value, an indication of directional trend of analyteconcentration, and/or a graphical representation of the estimatedanalyte data over a period of time, for example. Other representationsof the estimated analyte values are also possible, for example audio andtactile.

In some embodiments, annotations are provided on the graph; for example,bitmap images are displayed thereon, which represent events experiencedby the host. For example, information about meals, medications, insulin,exercise, sensor insertion, sleep, and the like, can be obtained by thereceiver (by user input or receipt of a transmission from anotherdevice) and displayed on the graphical representation of the host'sglucose over time. It is believed that illustrating a host's life eventsmatched with a host's glucose concentration over time can be helpful ineducating the host to his or her metabolic response to the variousevents.

In yet another alternative embodiment, the sensor utilizes one or moreadditional electrodes to measure an additional analyte. Suchmeasurements can provide a baseline or sensitivity measurement for usein calibrating the sensor. Furthermore, baseline and/or sensitivitymeasurements can be used to trigger events such as digital filtering ofdata or suspending display of data, all of which are described in moredetail in U.S. Publication No. US-2005-0143635-A1.

In one exemplary embodiment, the sensor can be calibrated by acalibration solution. For example, after the sensor system has beeninserted into the host, a calibration solution can be injected so as topass across the electroactive surface of the analyte-measuring electrodeand the sensor calibrated thereby. For example, the saline drip can bechanged to a known IV glucose or dextrose solution (e.g., D50—a 50%dextrose solution, or D5W—a 5% dextrose solution). In one embodiment, aknown volume of D5W is infused into the host at a known rate over apredetermined period of time (e.g., 5, 10, 15 or 20 minutes, or forshorter or longer periods). During and/or after the period of infusion,the sensor measures the signal at the analyte-measuring workingelectrode. The system, knowing the specifications of the infusedcalibration solution (also referred to as a calibration information insome embodiments), can calibrate the signal to obtain host's glucoseconcentration as is appreciated by one skilled in the art. In a furtherembodiment, two or more glucose or dextrose solutions can be infused,with a corresponding signal being measured during each infusion, toprovide additional data for sensor calibration. Calibration can beperformed after the sensor has first been inserted into the host, aftera break-in time, at two or more different levels (high/low), regularly,intermittently, in response to sensor drift/shift, automatically or anyother time when calibration is required.

In some circumstances, catheters are flushed with saline. For example,the analyte sensor system of the preferred embodiments can be flushedwith saline prior to application of control solutions, after which apredetermined amount of glucose solution is flushed by the sensor, asdescribed above, and the sensor is calibrated there from.

In still another embodiment, a blood sample can be withdrawn from anartery or vein, and used to calibrate the sensor, for example, by usinga hand-held glucose meter, by an automatic extracorporeal glucose sensorsuch as but not limited to in conjunction with an automated bedsideclinical chemistry device, or by sending the blood sample to theclinical laboratory for glucose analysis, after which the data is input(e.g., into the electronics associated with the sensor system).

In some embodiments, the sensor can be calibrated (and/or re-calibrated)during use (after initial calibration), for example, by withdrawing oneor more blood samples (also referred to as calibration information insome embodiments), through the catheter (see FIGS. 1 and 2) and used forcalibration of the sensor, such as by measuring the glucoseconcentration of the blood sample with an additional system, such as butnot limited to a hand-held glucose meter, optical methods or additionalelectrochemical methods. Blood samples can be withdrawn manually orautomatically; additionally or alternatively, blood samples arewithdrawn at regular intervals or at selected times, for example, usingan extracorporeal blood analysis device as described herein.

In another embodiment of sensor calibration (and/or re-calibration)during use, a calibration solution (e.g., 40 mg/dL equivalent glucose,D540 or D5W) can be flushed through or by the sensor to enablecalibration of the sensor (e.g., at one time, intermittently, orcontinuously), such as described in more detail above. In theseembodiments, calibration solution can be flushed manually orautomatically through the system; additionally or alternatively,calibration solution can be flushed at regular intervals or at selectedtimes. In one exemplary embodiment, the system can be provided with adual lumen, one for saline and another for the control solution.Additionally, the system is configured to automatically switch from thesaline to control solution and perform the real-time system calibration,and then switch back to the saline solution.

EXAMPLES Example 1 Glucose Sensor System Trial in Dogs

Glucose Sensor Systems of the Embodiment Shown in FIG. 1 were Tested indogs. The glucose sensors were built according to the preferredembodiments described herein. Namely, a first sensor (Test 1) was builtby providing a platinum wire, vapor-depositing the platinum withParylene to form an insulating coating, helically winding a silver wirearound the insulated platinum wire (to form a “twisted pair”), maskingsections of the electroactive surface of the silver wire,vapor-depositing Parylene on the twisted pair, chloridizing the silverelectrode to form a silver chloride reference electrode, and removing aradial window on the insulated platinum wire to expose a circumferentialelectroactive working electrode surface area thereon, this assembly alsoreferred to as a “parylene-coated twisted pair assembly.”

An electrode domain was formed over the electroactive surface areas ofthe working and reference electrodes by dip coating the assembly in anelectrode solution (comprising BAYHYDROL® 123, an aliphaticpolycarbonate urethane resin) and drying. An enzyme domain was formedover the electrode domain by subsequently dip coating the assembly in anenzyme solution (comprising BAYHYDROL® 140AQ, an aliphatic polyesterurethane resin, and glucose oxidase) and drying. A resistance domain wasformed over the enzyme domain by spraying the resistance domain solution(comprising a blend of CHRONOTHANE®-1020 (a polyetherurethaneurea basedon polytetramethylene glycol, methylene diisocyanate and organic amines)and CHRONOTHANE®-H (a polyetherurethaneurea based on polytetramethyleneglycol, polyethylene glycol, methylene diisocyanate, and organicamines)) on the sensor construct.

After the sensor was constructed, it was placed in the protective sheathand then threaded through and attached to the fluid coupler.

A second sensor (Test 2) was constructed in the same manner as thefirst, except that the silver wire was disposed within (e.g., coiledwithin) the fluid coupler. Accordingly, only the platinum workingelectrode (a single wire) was inserted into the catheter during theexperiment.

Prior to use, the sensors were sterilized using electron beam.

The forelimb of an anesthetized dog (2 years old, ˜40 pounds) was cutdown to the femoral artery and vein. An arterio-venous shunt was placedfrom the femoral artery to the femoral vein using 14 gauge catheters and⅛-inch IV tubing. A pressurized arterial fluid line was connected to thesensor systems at all times. The test sensor systems (test 1 and test 2)included a 20 gauge×1.25-inch catheter and took measurements every 30seconds. The catheter was aseptically inserted into the shunt, followedby insertion of the sensor into the catheter. A transcutaneous glucosesensor (control) of the type disclosed in U.S. Publ. No.US-2006-0155180-A1 was built and placed in the dog's abdomen accordingto recommended procedures. The dog was challenged with continuousincremental IV infusion of a 10% dextrose solution (“glucose challenge”)until the blood glucose concentration reached about 400 mg/dL.

FIG. 4 shows the experimental results. The thick line represents datacollected from the Test 1 sensor. The thin line represents datacollected from the Test 2 sensor. Diamonds represent data collected froma hand-held blood glucose meter (SMBG) sampled from the dog's abdomen.Raw glucose test data (counts) are shown on the left-hand Y-axis,glucose concentrations for the “SMBG” controls are shown on theright-hand y-axis, and time is shown on the X-axis. Each time intervalon the X-axis represents 29-minutes (e.g., 10:04 to 10:33 equals 29minutes). Immediately upon insertion into a catheter, each test sensorbegan collecting data with substantially no sensor equilibration time(e.g., break-in time). Each test sensor responded to the glucosechallenge substantially similarly to the control sensor. For example,each device shows the glucose signal increasing from about 3200 countsat 10:33 to about 6000-6700 counts at 11:31. Then, each device showed arapid decrease in glucose signal, to about 4700 counts at 12:00.Additionally, the response of the test sensors and the control sensorwere substantially similar (e.g., the majority of the test data wassubstantially equivalent to the SMBG data at each time point). Fromthese experimental show that an indwelling glucose sensor system (asdescribed herein) in contact with the circulatory system can providesubstantially continuous glucose monitoring in a clinical setting.

Example 2 Glucose Sensor System Trial in Pigs

Four glucose sensor systems of the embodiment shown in FIG. 1 weretested in a pig (˜104 lb), using the protocol described for Example 1,above. Glucose was continuously infused at increasing rates through adistally placed IV catheter until a readout of 300-400 mg/dl bloodglucose was achieved (total 300-ml of a 10% dextrose IV solution). FIG.5 shows the experimental results. Lines indicated the data from the foursensors (Test 1 through Test 4). Diamonds represent control measurementsmade with a hand-held glucose meter (SMBG). Raw glucose test data(counts) are shown on the left-hand Y-axis, glucose concentrations forthe “SMBG” controls are shown on the right-hand y-axis, and time isshown on the X-axis. Test results show that though the sensors varied insensitivity, each test sensor responded to glucose challengesubstantially similarly to the control sensor (SMBG). These experimentalresults show that an indwelling glucose sensor system (of the preferredembodiments) in contact with the circulatory system can substantiallycontinuously track glucose in a clinical setting.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. Pat. No.4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No. 6,001,067; U.S. Pat.No. 6,741,877; U.S. Pat. No. 6,702,857; U.S. Pat. No. 6,558,321; U.S.Pat. No. 6,931,327; U.S. Pat. No. 6,862,465; U.S. Pat. No. 7,074,307;U.S. Pat. No. 7,081,195; U.S. Pat. No. 7,108,778; and U.S. Pat. No.7,110,803.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. PublicationNo. US-2005-0176136-A1; U.S. Publication No. US-2005-0251083-A1; U.S.Publication No. US-2005-0143635-A1; U.S. Publication No.US-2005-0181012-A1; U.S. Publication No. US-2005-0177036-A1; U.S.Publication No. US-2005-0124873-A1; U.S. Publication No.US-2005-0115832-A1; U.S. Publication No. US-2005-0245799-A1; U.S.Publication No. US-2005-0245795-A1; U.S. Publication No.US-2005-0242479-A1; U.S. Publication No. US-2005-0182451-A1; U.S.Publication No. US-2005-0056552-A1; U.S. Publication No.US-2005-0192557-A1; U.S. Publication No. US-2005-0154271-A1; U.S.Publication No. US-2004-0199059-A1; U.S. Publication No.US-2005-0054909-A1; U.S. Publication No. US-2005-0112169-A1; U.S.Publication No. US-2005-0051427-A1; U.S. Publication No.US-2003-0032874-A1; U.S. Publication No. US-2005-0103625-A1; U.S.Publication No. US-2005-0203360-A1; U.S. Publication No.US-2005-0090607-A1; U.S. Publication No. US-2005-0187720-A1; U.S.Publication No. US-2005-0161346-A1; U.S. Publication No.US-2006-0015020-A1; U.S. Publication No. US-2005-0043598-A1; U.S.Publication No. US-2003-0217966-A1; U.S. Publication No.US-2005-0033132-A1; U.S. Publication No. US-2005-0031689-A1; U.S.Publication No. US-2004-0186362-A1; U.S. Publication No.US-2005-0027463-A1; U.S. Publication No. US-2005-0027181-A1; U.S.Publication No. US-2005-0027180-A1; U.S. Publication No.US-2006-0020187-A1; U.S. Publication No. US-2006-0036142-A1; U.S.Publication No. US-2006-0020192-A1; U.S. Publication No.US-2006-0036143-A1; U.S. Publication No. US-2006-0036140-A1; U.S.Publication No. US-2006-0019327-A1; U.S. Publication No.US-2006-0020186-A1; U.S. Publication No. US-2006-0020189-A1; U.S.Publication No. US-2006-0036139-A1; U.S. Publication No.US-2006-0020191-A1; U.S. Publication No. US-2006-0020188-A1; U.S.Publication No. US-2006-0036141-A1; U.S. Publication No.US-2006-0020190-A1; U.S. Publication No. US-2006-0036145-A1; U.S.Publication No. US-2006-0036144-A1; U.S. Publication No.US-2006-0016700-A1; U.S. Publication No. US-2006-0142651-A1; U.S.Publication No. US-2006-0086624-A1; U.S. Publication No.US-2006-0068208-A1; U.S. Publication No. US-2006-0040402-A1; U.S.Publication No. US-2006-0036142-A1; U.S. Publication No.US-2006-0036141-A1; U.S. Publication No. US-2006-0036143-A1; U.S.Publication No. US-2006-0036140-A1; U.S. Publication No.US-2006-0036139-A1; U.S. Publication No. US-2006-0142651-A1; U.S.Publication No. US-2006-0036145-A1; U.S. Publication No.US-2006-0036144-A1; U.S. Publication No. US-2006-0200022-A1; U.S.Publication No. US-2006-0198864-A1; U.S. Publication No.US-2006-0200019-A1; U.S. Publication No. US-2006-0189856-A1; U.S.Publication No. US-2006-0200020-A1; U.S. Publication No.US-2006-0200970-A1; U.S. Publication No. US-2006-0183984-A1; U.S.Publication No. US-2006-0183985-A1; and U.S. Publication No.US-2006-0195029-A1.

Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed Nov. 22, 1999 and entitled “DEVICE AND METHODFOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No. 11/335,879filed Jan. 18, 2006 and entitled “CELLULOSIC-BASED INTERFERENCE DOMAINFOR AN ANALYTE SENSOR”; U.S. application Ser. No. 11/334,876 filed Jan.18, 2006 and entitled “TRANSCUTANEOUS ANALYTE SENSOR”; U.S. applicationSer. No. 11/498,410 filed Aug. 2, 2006 and entitled “SYSTEMS AND METHODSFOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”; U.S.application Ser. No. 11/515,443 filed Sep. 1, 2006 and entitled “SYSTEMSAND METHODS FOR PROCESSING ANALYTE SENSOR DATA”; U.S. application Ser.No. 11/503,367 filed Aug. 10, 2006 and entitled “ANALYTE SENSOR”; andU.S. application Ser. No. 11/515,342 filed Sep. 1, 2006 and entitled“SYSTEMS AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

What is claimed is:
 1. A system for measuring glucose in a host and delivering medication to the host, the system comprising: a catheter configured for insertion into a host and configured to deliver medication to the host, wherein the catheter comprises an exterior surface; a continuous glucose sensor disposed at least partially on the exterior surface of the catheter, wherein the continuous glucose sensor is configured to generate sensor data indicative of glucose concentration; and sensor electronics operatively connected to the continuous glucose sensor, wherein the sensor electronics are configured to determine a glucose concentration.
 2. The system of claim 1, wherein the continuous glucose sensor is integrally formed on the exterior surface of the catheter.
 3. The system of claim 1, wherein the continuous glucose sensor is electroplated onto the exterior surface of the catheter.
 4. The system of claim 1, wherein the continuous glucose sensor comprises a working electrode and a membrane system covering at least a portion of the working electrode.
 5. The system of claim 1, wherein the working electrode comprises an exposed electroactive surface.
 6. The system of claim 1, wherein the catheter is configured to be operatively connected to an infusion pump.
 7. The system of claim 1, wherein in response to sensor data received from the continuous glucose sensor, the sensor electronics are configured to communicate a therapy recommendation to the infusion pump, wherein the therapy recommendation comprises information relating to insulin amount.
 8. The system of claim 1, wherein the continuous glucose sensor is configured to be used subcutaneously.
 9. The system of claim 1, wherein the sensor electronics are configured to substantially continuously determine the glucose concentration. 